Block 1

Question 1

Chronic granulomatous disease

Answer 1

• Mutation in NADPH oxidase complex
• Children typically detected because repeated bacterial infections in infancy
• When testing oxygen to superoxidase production using NBP test their white cells do not convert oxygen to superoxide
o Cells look white when challenged, normal cells will look blue
• Phagocytes fail to produce adequate levels of oxygen radicals and hydrogen peroxide upon phagocytosis of microbes

Question 2

Glucose 6-P dehydrogenase deficiency

Answer 2

• This enzyme is involved in the HMP shunt
• If mutation in this enzyme it blocks the conversion of oxygen to superoxide and gives child who is phenotypically like chronic granulomatous child
• Can cause increase susceptibility to infection

Question 3

MPO deficiency

Answer 3

• Deficiency in myeloperoxidase
• Not as severe because other antimicrobial agents can be produced
• Still causes increased susceptibility to infection

Question 4

Glutathione reductase, glutathione peroxidase deficiencies

Answer 4

• Need coupling of pathways for this to work

* Without coupling the conversion of oxygen to superoxide comes to a halt

Question 5

Chediak-higashi syndrome

Answer 5

• Abnormal fusion of phagosomes with lysosomes
• Failure to kill ingested microbes
• Impaired MPO
• Impaired myeloperoxidase
• Faulty lysozomal fusion

Question 6

Leukocyte adhesion deficiency (LAD)

Answer 6

• Group of disorders where interaction of leukocytes with vascular endothelium is disrupted
• Due to autosomal recessive mutation that results in faulty expression of CD18 (CD11a/CD18 and CD11b/CD18) are present on neutrophils and monocytes and are pivotal to attachment to endothelium for diapedesis into the tissues
• Loss of adhesive interactions greatly inhibits the ability of T cells to effectively mount immune responses, as manifested in the clinical disease lymphocyte adhesion deficiency (LAD).

Question 7

IRAK4 deficiency

Answer 7

• Increase sensitivity to certain infections
• Increased sensitivity to respiratory viruses and other agents
• Important to recognize that there are a number of inheritable mutations that lead to deficient innate immune responses.

Question 8

Mechanisms of immune evasion

Answer 8

o Pneumococcus
o Capsular polysaccharide inhibits phagocytosis
• Resistance to reactive oxygen intermediates in phagocytes
o Staphylococci
o Production of catalase which breaks down reactive oxygen intermediates
• Resistance to complement activation (alternative pathway)
o Neisseria meningitides
 Sialic acid expression inhibits C3 and C5 convertases
o Steptococcus
 M protein blocks C3 binding to organism and C3b binding to complement receptors
• Resistance to antimicrobial peptide antibiotics
o Pseudomonas
o Synthesis of modified LPS that resists action of peptide antibiotics
• Prevent cell sloughing
o Neisseria gonorrheoeae
o Increase adhesion molecules on vaginal epithelial cells – decreases sloughing

Question 9

Pathogen sabotage of complement

Answer 9

• Pathogens have learned to use and abuse complement components
• Evasion from destruction by complement
• Evolved ways of attracting factor H to the surface
o Example – candida yeast
o Factor H will stop complement in its tracks – complement cannot be activated
• Helicobacter incorporates the MAC
o Lytic important for destruction of helicobacter
o CD59 is incorporated
• Some bacteria have found ways to attach sialic acid to their surface (taken from dying cells or making sialic acid), once there is sialic acid on the bug properitin does not like to bind
 Not a good surface for the fixing the complement cascade

Question 10

Hemolytic Uremic Syndrome

Answer 10

• Thrombocytopenic, microangiopathic (TMA) hemolytic anemia with kidney injury
• Thrombocytopenic = low platelets
• Hemolytic anemia = Red blood cells lysing (breaking open)
• Microangiopathic = caused by narrowing or obstruction in small blood vessels
• Uremic = retention in the blood of waste products normally removed by the kidneys
• Atypical or recurrent Hemolytic Uremic Syndrome is caused by complement system “deregulation”
o Low levels of or dysfunctional complement cascade inhibitors
o Factor I, Factor H and MCP are important in the atypical hemolytic uremia syndrome
o Specifically the alternative pathway
• *‘typical’ HUS, or diarrhea associated HUS, caused by a Shiga toxin produced by E.coli bacteria, is a purely pediatric illness
o Diarrheal HUS is a one-time thing, kids recover
o If no bacteria or shiga toxin is identified in a child’s stool then diagnosis of aHUS is made
• HUS is permanent genetic mutation causes low levels of or dysfunctional factors H, factor I, or membrane co-factor (MCP)
• Some environmental ‘trigger’ event causes initial injury to lining of blood vessels (endothelium), activating complement cascade
o Once the cascade has been activated it can not be shut off
o Triggers include infections, pregnancy, medications, surgical procedures, and birth control pills.[4] importantly, gastroenteritis is a potential trigger of aHUS
• Uncontrolled complement activation, MAC incorporation and damage to cells lining blood vessels
• Cell injury attracts white blood cells and exposes thrombogenic parts of cells
• Platelet accumulation and activation of coagulation cascade (formation of clots)
o Thrombocytopenia
 Multiple intracapillary glomerular thrombi
o Platelets are main component of clot, creating lots of clots low levels of platelets
• Clots and narrowing of blood vessel cause injury to blood cells passing through (lysis)
o Hemolytic Anemia
• Poor filtration across glomerular membrane
o Uremia or Renal failure
 Decreased or absent urine production
 Become uremic and have retention of waste products, potassium, urea, creatinine
 Elevated creatinine – can not filter across the membrane
• Genetics
o Abnormal genes causes a problem with the factors
o Unclear if monogenic or polygenic
o Most commonly autosomal dominant
o Mutations in genes for FH and FI (produced by liver), and MCP (glomerular expression)
 FH mutations most common
 aHUS onlt develops in ~ 50% of patients with a factor H mutation
 Nearly 70% with aHUS have a mutation in one of the currently defined genes
• Prognosis
o Recurrent and persistent
o Renal failure
• Treatment
o Supportive Care
 Blood transfusions
 Fluid, electrolyte, and blood pressure management
 Dialysis
o Correct abnormality in complement pathway
 Plasma therapy
 Complement cascade inhibitor- Eculizimab
• Medication used more commonly for aHUS
 Organ transplant

Question 11

C3 deficiency

Answer 11

• Consequence: loss of opsonization and MAC (its all gone –complement does not function)
• Clinical manifestations: pyogenic infections, especially Staph, Neisseria
o Problems with all extracellular bacteria
• C3 deficiency is the most debilitating, not surprising considering its central and indispensable role in the cascade, potentially leading to severe bacterial infections

Question 12

C1 inhibitor (C1NH) deficiency

Answer 12

• Consequence: lose C1 and kallikrein regulation; kininogen cleaved to release bradykinin
o C1NH is the molecule that dissociates C1q from C1R and C1S
o Also an inhibitor of the coagulation cascade
o Without this inhibitor will have a lot of bradykinin released – molecule that induces vasoconstriction
 Cannot use Benadryl or epinephrine because different pathway
 Can only be cured by fresh plasma or adding C1 inhibitor
• Clinical manifestations: hereditary angioedema (HAE or HANE)
• C1-INH (or C1 esterase inhibitor) deficiency leads to ‘hereditary angioneurotic edema,’ or HANE (more commonly HAE).
o C1-INH is also an inhibitor of bradykinin production, which in combination with a proteolytic fragment of C2 (C2 kinin or C2b) can lead to intermittent acute edema in skin and mucosal tissues, potentially leading to airway obstruction.

Question 13

CD59 deficiency

Answer 13

• Consequence: no inhibition of MAC
o Inhibitor of MAC, found on the surface of the cells
• Clinical manifestations: hemolysis, thrombosis (PNH: paroxysmal nocturnal hemoglobinuria)
o Without inhibition of MAC, can have PNH – this is life threating
• Deficiency in one of the MAC components leads to heightened susceptibility to Neisseria infections
• A deficiency in DAF or CD59 (direct, via absence of the gene or indirect, via the absence of the enzyme that forms GPI (glycophosphatidylinositol) tails) causes paroxysmal nocturnal hemoglobinuria (PNH)
o Characterized by intravascular hemolysis and presumably caused by unregulated MAC formation.
o Patients have dark urine, which is most pronounced in the morning (due to pH changes in the blood at night resulting in increased MAC production as well as overnight urine concentration.)

Question 14

C1qrs, C4, C2 deficiency

Answer 14

• Consequence: lose classical pathway
o Alternative pathway can take over, for immune defense it is not that big of problem
• Clinical manifestations: SLE (lupus)
o Without removing the immune complex you can end up with immune complex disease
o Also has a strong association with lupus
o If C1q is missing it is an association with lupus – apoptotic cells are not being removed as efficiently as they are when C1q is around
o Tissue damage and failure to remove the bleb – association with autoimmune disease
• C2 and C4 deficiencies do not generally result in heightened susceptibility to infections, but there is an increased risk of immune-complex diseases (like SLE), perhaps initiated by a delay in uptake and removal of antibody-antigen complexes
• Note that C2 deficiency is the most common complement disorder.

Question 15

Factor H, I deficiency

Answer 15

• Consequence: C3 deficiency, factor H mutations important in many clinical situations
o Factor H is important inhibitor of C3 convertase
o When you have deficiency of Factor H and Factor I you will have a C3 deficiency
o Complement will get used up because you will have amplification
o Factor H and I are competing with Factor B to limit the amount of activation of the complement cascade
• Clinical manifestations: infections, inflammation, macular degeneration, AHUS
o Leads to same thing as C3 deficiency
• Factor I or Factor H deficiency actually leads to a C3 serum depletion by the reduced capacity of the system to inhibit C3b,Bb convertases once they spontaneously form by the ‘tickover’ mechanism
o Because Factor H is involved in dampening responses, continual activation of the alternative pathway in Factor H-deficient (or even certain alleles) folks is associated with aging macular degeneration (AMD).
• Mutations found in Factor H are associated with macular degeneration

Question 16

PIG-A deficiency

Answer 16

• Loss of GPI anchor results in disease
• PIG-A - enzyme that puts the lipid tail onto the backend of certain molecules
o Molecules on the surface with phosphatidylinositol N-acetyl glucosaminyl transferase subunit A tails
o This enzyme that puts the lipid tails on can be defective
• All of the GPI linked molecules will not be on the surface
o Two important GPI linked molecules are CD59 and DAF
• This leads to PNH (paroxysmal nocturnal hemoglobinuria hemoglobinuria)
o This is worse PNH than if there is simply a defect in the gene that encodes CD59
o Just missing CD59 will have PNH, worse if missing both CD59 and DAF
• Deficiency in an enzyme (PIG-A) results in failure of expression of ALL gpi-linked proteins (e.g. CD59 and DAF)
• When these two are missing PNH is exacerbated (CD59 deficiency itself leads to PNH, but the disease is exacerbated when DAF is missing as well).
• PIG-A problems may come from total deficiency or somatic mutations

Question 17

PNH

Answer 17

• If just missing CD59, MAC does not form very often on its own but it cam
• Especially at night when pH of blood changes, encourages molecule of MAC to form
• Can insert in RBC and end up with hemolysis
• Without DAF in addition to deficiency in CD59 there will be a defect in the blocking of the amplification loop that is forming on cells
• Cd59 is on surface on RBC, without it will have some deposition of C3b on the surface of the RBC
• Treated with Eculizamab because it will block the splitting of C5 into C5b and C5a
• Given their deficiency in surface CD55, PNH erythrocytes are susceptible to complement activation through C3 tick over and the alternative pathway, as well as through any other complement pathway
• After initial C3 activation and subsequent C3b binding to erythrocyte surface, the complement cascade may proceed toward the MAC formation, which is not inhibited due to the lack of CD59
• As a result PNH erythrocytes succumb because of MAC-mediated intravascular hemolysis

Question 18

Hereditary angio(neurotic) edema

Answer 18

• Inhibitor is part of the bradykinin cascade and complement cascade
• Activation of kallikrein → cleavage of kininogen to generate bradykinin, vasoactive peptide
• Activation of proactivator → cleavage of plasminogen to generate plasmin → cleavage of C2b to generate C2 kinin, vasoactive peptide
• Cleavage of plasminogen to generate plasmin → activation of C1 → cleavage of C2 to generate C2b → cleavage of C2b to generate C2 kinin, vasoactive peptide
• Treatment of HAE
o Fresh plasma
o Purifies C1 inhibitor from plasma

Question 19

Kidney transplants

Answer 19

Antibodies play the major role in hyperacute and chronic organ rejection (typical rejection is T cell-mediated)
o The typical acute rejection of a kidney graft is usually due to cytotoxic T cell
 Acute and chronic rejection of graft can be due to antibodies
• Blocking C’ activation can ameliorate rejection episodes
• Complementary determining regions – heavy and light chain V will be different for each antibody
• Even our monoclonal antibodies will be different because of the diverse region
• Eculizumab being used in HUS, PNH and also being used in renal transplantation
 If you detect antibodies against the donor kidney – MHC antigens – can use Eculizumab and block the destruction of the kidney by blocking the formation of MAC

Question 20

Encapsulated bacteria

Answer 20

• E.g. Neisseria
• MAC is important for the defense against Neisseria
• When we use Eculizumab we can often end up with infections of Neisseria
• Neisseria have anti-opsonic functions of their capsules
• Whenever we use Eculizumab it is good to vaccinate against Neisseria so that the patient has antibodies
o Lost C5a and lost MAC
o Only have opsinization and whatever inflammation from C3a
o Need to rely on vaccinating so we ensure we have antibodies
• C’ is important for defense (MAC especially) so we must vaccinate C’ suppressed people
• Encapsulated bacteria resist uptake by neutrophils and avoid engulfment
• Encapuslated bacteria like Neisseria resist phagocytosis, so MAC is quite important for defense against these nasty bugs.
• Vaccination will generate antibodies that fix C’ and C3b, hopefully overcoming the phagocytosis resistance by opsonization

Question 21

Penicillin hypersentitivity

Answer 21

• Penicillin is a small, beta-lactam ring antibiotic with potent bactericide activities.
• It blocks the last step of cell wall biosynthesis in Gram-positive bacteria and has proven instrumental in the success of chemotherapeutical management of infectious diseases.
• Penicillin is a hapten that normally cannot induce an immune response.
• It is also a drug, however, that binds to plasma proteins (“carrier”) at a certain concentraiton shortly after administration.
• While most people are naturally tolerant to their plasma proteins, in some the drug coupled to its carrier induces immune recognition and, typically, IgE production (sensitization).
• Upon re-exposure to the drug, circulating IgE can bind to the free, soluble penicillin (hapten recognition), the complex is bound by Fce receptors on mast cells which induces rapid degranulation and release of histamine and other inflammatory mediators that cause an immediate hypersensitivity reaction, occasionally leading to fatal anaphylactic shock. 3-6% of people react to penicillin at least in a skin test, and about 0.004-0.015% develop anaphylactic shock.

Question 22

Omenn syndrome

Answer 22

• SCID caused by Rag-1 or Rag-2 mutations
o If the recombinase (RAG1 or RAG2 gene mutations) is defective then will not have recombination and will not create immunoglobulins and T cell receptors
o When you do not have recombination, you will not be able to progress in development of lymphocytes
 Not only lymphocytes with TCR, no lymphocytes at all
• SCID – Severe Combined Immune-Deficiency (because you do not have T cells or B cells)
• Symptoms:
o Erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, hepatosplenomegaly
• Laboratory:
o No B-cells, oligclonal T-cells, hyper IgE, eosinophilia
• Cause:
o Hypomorphic RAG gene mutations
• Treatment:
o Bone marrow transplantation, gene therapy (exp)
• RAG-1 mutations affect DNA binding or catalytic activity
• RAG-2 mutations affect chromatin accessibility
o RAG 2 has unique domain, if this is mutated that results in catalytically active complex that cannot be targeted appropriately
• Some mutations will be hypermorphic – result in significant loss of activity
• Some lower levels rearrangement can happen can generate a few T cells – these will expand and will give rise to relatively normal looking lymphocyte number but severely reduced diversity of clonality (autoclonality)
o Losing diversity – lose ability to fight diverse antigens and lost many regulatory features and networks in lymphocyte activity
o Hyper-activity of immune system – hyper reactive scenarios
o Due to reduction in diversity and disturbing lymphocyte regulatory pathways

Question 23

Combined scid + radiation sensitivity

Answer 23

• Caused by Artemis/DNA ligase 4 mutations
o Not able to join the ends because of defects in NHEJ
o RAG activity is intact, defect in artermis or ligase 4
• Symptoms:
o Neonatal scid
 Childhood EBV-lymphoma
o Adult-onset immunodeficiency
o Microcephaly (Ligase 4)
o Radiation sensitivity
o Genomic instability
• Laboratory:
o No T/B-cells
o No, or little, circulating Ig
• Cause:
o Complete or hypomorphic Artemis or hypomorphic DNA ligase 4 gene mutations
• Treatment:
o Bone marrow transplantation, gene therapy (exp)
• These patients are radiation sensitive due to inability to fix DNA end breaks
o Cannot repair DNA breaks, NHEJ is universal pathway important in gene rearrangement and in general DNA break repair

Question 24

Type 2 hyper IgM syndrome

Answer 24

• Deficiency associated with AICDA mutations
o Process occurring in activated B cell
o Can generate primary responses, cannot switch to other isotypes and cannot switch to higher level antibodies
• Autosomal
• Symptoms:
o Repeated bacterial pneumonia, otitis, lymphadenopathy
• Laboratory:
o Normal B/T-cells,
o Hyper IgM,
o No other Ig isotypes
• Cause:
o Inactivating AID gene mutations
• Treatment:
o I.v. immunoglobulin
• Will generate the germinal centers because the activation of the process is normal
• Inside the germinal centers the process is defective because of the mutation of enzyme

Question 25

Type 1 HIGM

Answer 25

•	X-linked or autosomal 
•	Symptoms:
o	Repeated bacterial pneumonia, otitis,
o	Penumocystis infection
•	Laboratory:
o	Normal B/T-cells,
o	No leukocytosis w/infection
o	Hyper IgM,
o	No other Ig isotypes
o	No CD40L on T-cells
•	Cause:
o	CD40L or CD40 gene mutations
o	Inability of T cell help 
•	Treatment:
o	I.v. immunoglobulin
•	Defect in forming germinal center 
o	AID is not induced because there is a defect in forming the germinal center 
o	If AID would have been induced it would perform appropriately but not induced because no germinal center 
•	Only produce IgM, no other isotypes 
o	Even if you vaccinate, you can not produce high affinity antibodies 
•	There are no germinal centers

Question 26

Ankylosing Spondylitis

Answer 26

• Approximately 90% of AS patients express the HLA-B27 genotype, suggesting a strong genetic association.
• There is no direct test to diagnose AS.
• A clinical examination using MRI and X-ray studies of the spine which show characteristic spinal and sacral region changes is used.
o In early stages there is inflammation in places of backbone in sacral region
o Eventually will be calcified and fused
• This is combined with genetic marker blood test (HLA testing are the major diagnostic tools.
• Antigen-dependent theories suggest a specific combination of antigen peptide sequence and the binding groove of HLA
o Arthritogenic peptide hypothesis suggests that HLA-B27 has a unique ability to present peptide specific to joints, to autoreactive cytotoxic T cells.
 T cells exacerbate inflammation in lower back
o Molecular mimicry hypothesis suggests that cross reactivity between some bacterial antigens Klebsiella and self-peptide can break tolerance and lead to autoimmunity.
• Antigen-independent theories to the unusual biochemical properties that HLA-B2
o The misfolding hypothesis suggests that slow folding during HLA-B27’s B2 association or B27 heavy chains tend to dimerize and accumulate in the ER resulting in ER stress
o NK hypothesis cell surface B27 heavy chains and dimers can bind to regulatory immune receptors such as members of the killer cell immunoglobulin-like receptor family promoting the survival and differentiation of pro inflammatory leukocytes in disease
• Non MHC involvement in the disease
o ERAP1 polymorphisms of ER aminopeptidase involved in peptide trimming before HLA-B27 results in aberrant class I presentation of antigenic peptides.
 If you had one allele of the ERAP1 you might trim a peptide that can cause exacerbation of the disease
o IL-23 was shown to facilitate development of inflammation other models of immune pathology.

Question 27

Pathogen sabotage – MHC I

Answer 27

•	Blocks peptide entry to ER 
o	Herpes simplex virus 1 
	ICP47 
	Blocks peptide binding to TAP 
o	Human cytomegalovirus (HCMV) 
	US6 
	Inhibits TAP ATPase activity and blocks peptide release into ER 
o	Bovine herpes virus 
	UL49.5 
	Inhibits TAP peptide transport 
•	Retention of MHC class I in ER 
o	Adenovirus 
	E19 
	Competitive inhibitor of tapasin 
o	HCMV 
	US3 
	Blocks tapasin function 
o	Murine cytomegalovirus (CMV) 
	M152 
	Unknown 
•	Degradation of MHC class I (dislocation) 
o	HCMV 
	US2 
	Transports some newly synthesized MHC class I molecules into cytosol 
o	Murine gamma herpes virus 68 
	mK3 
	E3 ubiquitin ligase activity 
•	Binds MHC class I at cell surface 
o	Murine CMV 
	m4 
	interferes with recognition by cytotoxic lymphocytes by an unknown mechanism

Question 28

MHC Class II deficiency

Answer 28

•	All class II proteins (DP, DQ, DR) be affected
•	Transcription factors that are important for production of class II molecules 
•	Defect in the transcription factors so they will not be expressed 
•	When class II is absent patients have no CD4 cells.
•	The most common form of class II deficiency is the absence of certain transcription factors specific for class II gene promoters. 
o	These patients lack CD4 cells because of a failure of positive selection by thymic class II molecules.

Question 29

MHC Class I deficiency

Answer 29

• All of the proteins (A,B,C) not be expressed at the cell surface
• Deficiency seen with highest proportion is TAP deficiency
o Just like virus blocking TAP
o No class I molecules can get to surface
• When class I is not found at the cell surface, patients have CD4 cells but no CD8s
• The most common deficiency for class I is a mutation in TAP; loss of the peptide supply to the ER constipates class I molecules in this organelle and they never get to the surface (there are very rare deficiencies in tapasin and beta2-microglobulin as well that lead to the same phenotype)
• These patients have no CD8 T cells either, because recognition of class I on the thymic epithelium is required for CD8 cell positive selection.

Question 30

Association of DQ2 with celiac disease

Answer 30

• Gluten is composed of the repeat sections cause gliadin
• When gliadin is taken across epithelial barrier associates with APC and DQ2
• When gliadin comes into mucosal environment there is enzyme called transglutaminase that will change glutamate to glutamic acid
• This makes a tight association with DQ2
o Glutamic acid can make ionic bonds with positively charged residues found in the DQ2
• This will stimulate CD4 T cells
o These have never been tolerated to gliadin because never see in thymus
• This will potentiate celiac disease through production of pro-inflammatory cytokines
• Transmidation of the gliadin peptide and activation of the gliadin specific T cell
• Activation of plasma cells and other lymphocytes
• Cytokines released by activated lymphocytes lead to damage to intestinal epithelium

Question 31

Genetic mutations in commitment genes underlie leukemiagenesis

Answer 31

• Many of the mechanisms, if they go wrong or being hyperactive or inactivated they can underlie oncogenesis in that lineage
• Chromosome translocations and activating point mutations of Notch-1 are found frequently in T-ALL
o Notch receptor truncated by genetic mutations – results in deregulated hyperactive reaction, no longer dependent on ligand interaction to signal
o Translocation – the gene encoding Notch receptor translocate via the T cell receptor gene
• Chromosome translocations and point mutations that disable Pax5, EBF are found frequently in B-ALL
o Inactivating Pax-5
o Result in the loss of the transcription factors from early B cell developmental stage

Question 32

AIRE mutations

Answer 32

• Thymic medullary epithelial cells express a large number of tissue specific genes
• By expressing tissue specific genes, these cells developing in thymus will encounter all of the self-antigens produced in the body
• There is transcription factor AIRE that is occasionally mutated in humans
o When mutated potential highly reactive self autoimmune clones can differentiation and become T cells
o Can give rise to autoimmune phenotype
• Hs.: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APCED)
• Human AIRE mutation:
o Endocrinopathy (Addison’s disease, hypoparathyroidism, hypogonadism, diabetes)
 Mucocutaneous cadidiasis
o Alopaecia (autoimmune)
o AIRE allows the ectopic expression of many (though not all) genes in medullary thymic epithelial cells (mTEC)
• An unusual mutation in the transcription factor autoimmune regulator (AIRE) causes Type 1 autoimmune polyendocrinopathy.
o AIRE appears to regulate expression of many genes in thymic medullary epithelial cells which present these ectopic proteins as tolerizing self antigens.
o In the mutant patients, lack of thymic self antigen presentation can lead to breakdown of central tolerance causing primarily autoimmune disorder of endocrine organs, skin or liver.

Question 33

Foxp3 mutations

Answer 33

• Foxp3 is required for the development of CD4+ CD25+ Regulatory T-cells
• Foxp3 is an X linked transcription factor
• When Foxp3 is mutated the regulatory T cells do not develop
o Gives rise to autoimmune phenotype
• Mus: scurfin mutation (x-linked)
• Hs: immune dysfunction polyendocrinopathy enteropathy X-linked syndrome (IPEX)
• Human Foxp3 mutation:
o Enteropathy
o Type 1 diabetes
o Eczema
• Another inherited autoimmune disease is the X-linked autoimmunity-allergic dysregulation syndrome, caused by mutations in the FoxP3 locus.
o FoxP3 is a transcription factors that is necessary for the development of CD4/CD25-positive, regulatory T-cells (Treg).
• The disease is more severe than Type 1 autoimmune polyendocrinopathy and could be fatal in affected males.

Question 34

Developmental checkpoints regulate lymphopoiesis

Answer 34

• 1. Commitment
o IL-7, SCF
• 2. Pre-AgR selection
• 3. AgR selection

Question 35

Primary immunodeficiency

Answer 35

• X-SCID
o Gamma chain deficiency
o At pro lymphocyte stage
• ADA-def
o At development of pro and pre lymphocyte stage
• RAG-def Artemis
o At development of immature lymphocyte stage
• Selectively affect antigen specific differentiation of the B and T lineages
o ZAP-70 def, MHC def
o Btk def
o X-agammaglobulinaemia

Question 36

X-linked severe combined immunodeficiency (x-scid)

Answer 36

• Due to a mutation in the gene encoding the common gamma-chain of cytokine receptor.
• This receptor responds to IL-2, IL-4 and IL-7; the last one is critical for pro-lymphocyte proliferation

Question 37

Autosomal scid

Answer 37

• Caused by adenosine deaminase (ADA)-deficiency, by JAK-3 deficiency (IL-7 signaling cascade) and by deficiencies in the enzymes involved in mediating VDJ recombination, such as RAG-deficiency (Omen syndrome) or DNA repair enzymes involved in effective joining of the Ig and TCR gene segments such as the DNA-dependent protein kinase and Artemis.

Question 38

Bruton x-linked agammaglobulinaemia

Answer 38

• Selective B-cell-defects occur in Bruton x-linked agammaglobulinaemia due to Bruton tyrosine kinase (Btk)-deficiency and in B-cell linker protein (Blink)-deficiency which impair BCR signaling, as well as in rare Ig alpha, lamba 5 or IgM-deficiencies, which impair pre-BCR expression

Question 39

Di George syndrome

Answer 39

• The most common cause of selective T-cell-defects is aplasia of the thymic stroma in DiGeorge syndrome caused usually by chromosomal deletions that impair development of the 3rd-4th pharyngeal arches

Question 40

LAT mutation

Answer 40

• TCR signaling is defective in rare ZAP-70 or Linker for activation of T-cells (LAT)-mutant patients; the former inhibits differentiation of CD8+ T-cells the latter causes not only T-cell deficiency but also a severe imbalance in the generation of TH1 and TH2 cells.

Question 41

Autoimmunity

Answer 41

•	Most immune responses are self-destructive through the inflammatory response or virus specific T-cell cytotoxicity, however, they usually cause limited damage.  
•	utoimmune conditions arise when both negative selection of immature lymphocytes (central deletion) and maintenance of peripheral tolerance (clonal anergy or regulatory T-cell function) fail.
•	Organ-specific autoimmune diseases include: 
o	Type 1 diabetes, Grave's thyroiditis, multiple sclerosis, pemphigus vulgaris (skin disease), etc. 
o	It is believed that in these disorders self antigens, which are not expressed in the thymus or bone marrow, cannot delete immature T and B-cells, respectively.  
o	Although these cells should still remain unresponsive, if expression of co-stimulatory molecules happens to be induced in the target organs (e.g. during an infection), these organs can become effective targets to self-reactive lymphocytes. 
o	The ensuing tissue damage and inflammatory response will further amplify and prolong the self-destruction, frequently in a tissue-specific manner.
•	Systemic autoimmune diseases include: 
o	Lupus (SLE), rheumatoid arthritis, scleroderma, etc. 
o	The cause of these diseases remains obscure. 
o	Chronic T-cell activation and proliferation can result in the release of stimulatory cytokines that can activate autoreactive B-cells and induce (self) antigen-specific affinity maturation of autoantibodies. 
	This can eventually lead to systemic autoimmune disorders.

Question 42

Losing negative regulation of immune system

Answer 42

• PTEN or SHP-2 (cancer); SHP-1 or LYP (autoimmunity)
• Mutations in some of these phosphatases
• Mutations lead to cancer – over proliferation of immune cells, leukemia and lymphoma
• Autoimmunity – over-reactivity of the T cells, driving inappropriate proliferation or immune responses
o Limits the break
o More proliferation and driving of the immune response

Question 43

Mutations in CD40

Answer 43

• Hyper IgM syndrome
• Without CD40 ligand there will be no class witching
• Will only have IgM in the blood stream
• Because of loss of function of Cd40 L and CD40 and the signaling the drives the proper T cell help
• Patients with mutations in CD40L present with X-linked hyper-IgM syndrome
• B cell presents antigen to helper T cell → helper T cell is activated, expresses CD40L, secretes cytokines → B cells are activated by CD40 engagement, cytokines → B cell proliferation and differentiation

Question 44

HLH – hemophagocytic lymphohistiocytosis

Answer 44

• Perforin deficiency causes hemophagocytic lymphohistiocytosis (HLH)
• Genetic or acquired (infection)
• Fever, splenomegaly, haemophagocytosis, hypertriglyceridaemia and hypofibrinogenaemia
o Hyper activated and angry macrophages, phagocytizing and secreted many pro-inflammatory cytokines
• High serum levels of IFN-gamma, TNF-alpha, IL-6, IL-10, and M-CSF.
• CD8 T cells are not able to clear viral infection
o CD8 cells secrete interferon gamma
o IFN-gamma communicates with macrophages, macrophages are very angry and start phagocytosis and secreting own inflammatory cytokines
 TNF-alpha
 IL-6
 M-CS
• Immunosuppressants and chemotherapy have been standard of care for HLH, but understanding disease mechanism has suggested alternative – anti-IFNgamma
o Anti-IFN-g reverses the toxicity associated with loss of perforin

Question 45

Job’s syndrome

Answer 45

• Hyper-IgE Syndrome, HIES
• Inherited mutation in T helper cell function
• Autosomal dominant mutation in STAT3
• Mutations in STAT3 lead to defects in IL-6 signaling and the TH17 lineage
o STAT3 function is important in signaling pathway that lead the Th17 development
o Il-6 and IL-21 signal through JAK, STAT signaling pathway that involves STAT3
• Loss of STAT3 function (autosomal dominant mutations) inhibits Th17 development
o Lost STAT 3 function and cannot induce differentiate gene expression in the Th17 cells
o Cannot make Il-17 cannot mediate effector function
• Loss of Th17 cell function → inability to respond to extracellular bacterial and fungal infections.
• Symptoms
o Job Syndrome (HIES) is a rare primary immunodeficiency disease
o Recurrent staphylococcal skin abscesses
o Recurrent fungal lung infections (Candida)
o Eosinophilia (a high number of eosinophils in the blood)
o High serum levels of IgE.
• Mutations in STAT3 can lead to a disease in which there are high levels of IgE in the serum (usually there is essentially no IgE), and a defect in the elimination of extracelluar bacteria leading to S. aureus skin abcesses (leading to boils, like Job’s) and bacterial pneumonia.
• The defect in IgE synthesis is not understood, but since STAT3 is associated with other signaling receptors, like IL-21 which is important in B cell stimulation by Tfh cells, there may be a problem with regulation of the Ig class switch

Question 46

AID deficiency

Answer 46

• The enzyme called the activation-induced cytidine deaminase (AID) has been shown to be absolutely required to initiate the mutations, and a bit surprisingly the isotype switch
• Humans lacking this enzyme only produce IgM (no switch), do not have mutated V genes, and fail to acquire antigen-specific, high-affinity antibodies.
• This phenotype is similar to the patients with a CD40L deficiency, except that AID-deficient patients are still capable of forming germinal centers and these are much larger than typical germinal centers.

Question 47

Vitamin A and D deficiency

Answer 47

• Decreased numbers of 47+
• T cells in the LN, cells fail to migrate
• Inflammation increases
• Decreased synthesis of IgA

Question 48

Diseases associated with defective mucosal tolerance

Answer 48

•	Food allergy or asthma
•	 Celiac disease (gluten sensitive enteropathy)
•	 Inflammatory bowel diseases
o	Crohn’s disease
o	Ulcerative colitis

Question 49

Celiac disease

Answer 49

• Celiac disease is an autoimmune disorder of the small intestine.
• It manifests as blunting of villi, crypt hyperplasia and lymphocyte infiltration of the crypts.
• The enzyme tissue transglutaminase modifies peptides from gluten (gliadin) such that they can bind and be presented by MHC Class II molecules.
• CD4 T cells are activated resulting in an inflammatory response that leads to atrophy of the villi lining the small intestine.
• This condition leads to malabsorption (inability to absorb nutrients) and may also cause anemia, bacterial overgrowth, immune defense failure and other conditions

Question 50

Inflammatory bowel disease

Answer 50

• Chron’s disease and ulcerative colitis
• Chron’s Disease
o Histology/anatomical location – skip lesions
o Main mediators of disease – Th1, Th17
o Noteworthy features – antiflagellin antibodies (C. Elson)
• Ulcerative colitis
o Histology/anatomical location – colon, rectal
o Main mediators of disease – NKT cells, IL-13
o Noteworthy features – patients have increased IL13R-alpha-2 expression .
• Both conditions involve chronic inflammation with elevated number of activated T cells

Question 51

Septic Shock

Answer 51

• Cytokines produced too high
o Overwhelming burden of LPS stimulating TLR 4 on macrophage – cytokine storm release
o Can overwhelm the system and cause shock or death
• Cytokine overproduction can lead to “cytokine storm” (as in sepsis)  shock/death (systemic inflammatory response syndrome (SIRS))
• Response to LPS (gram negative bacteria)
o TLR 4 responds by making cytokines and chemokines
o Temporal distribution of production of cytokines
 Often times overlapping
 Inducing synergistic up-regulation of certain activities
 Overwhelming exposure to cytokines can be lethal
o TNF, IL-1, IL-12 all respond to LPS gram negative infection
o Redundancy and other cytokines being made – difficult to stop sepsis

Question 52

Rheumatoid Arthritis

Answer 52

• Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by severe joint destruction, pain, and disability, involves reactive inflammation and destruction of bone, cartilage, and the synovial membrane of the affected joint
• Cytokine mediated disease
• Inflammation, terrible disfiguration of the joints
• Synovia of the joint becomes inflamed, has lots of cytokines in it
• TNF and IL-1
o These cytokines are produced primarily by macrophages and fibroblasts in the synovial fluid
• Have inflamed synovial membrane, full spectrum of cells acting
o T lymphocytes an macrophages acting
• Synovial fluid with neutrophils
• TNF antagonists used as treatment
• There are two types of TNF inhibitors used clinically: engineered soluble receptor and monoclonal antibodies to TNF (both scavenge TNF and prevent its interaction with cell-associated receptors)

Question 53

Gout

Answer 53

• Inflammasome activation in gout
• In joints IL-1 plays important role in gout
• Bone erosions in the joints – primarily of the foot
• In the case of gout, what triggers it is overproduction of MSU crystals
o These crystals are taken up and activate the inflamasome – NALP3
o Multimerizes and recruits enzyme called caspase 1
o In response to another signal (PRR) you could have MyD88 induction
o Once caspase 1 is triggered, it can act on pro- IL-1 beta to cleave it
o Active IL-1 beta is produced and released into the system
• Rilonacept used for treatment of gout (IL-1 trap fusion protein)

Question 54

CAPS

Answer 54

• Group of related disorders due to mutations in NALP3 that lead to increased IL-1 production
o These people have gain of function mutation in inflammasome so the inflammasome is turned on all of the time
o Making caspase 1 active all of the time
o Any time have pro-IL Beta will be cleaved and release to IL-1
• IL-1 production (e.g., Muckle-Wells); rIL-1ra and Rilonacept used therapeutically.
• Inflammasome signaling (NALP3 = NLRP3) leads to the processing of pro-IL-1beta (inactive) to the active, mature form of IL-1beta

Question 55

Muckle Wells Syndrome

Answer 55

• Mutation in NLRP3
• Moderate low-grade fevers, starting in infancy; rashes during infancy
• Symptoms triggered by cold, stress, or unknown factors
• Progressive, significant hearing loss starting in adolescence
• Many develop amyloidosis from elevated serum amyloid; kidney failure
• Joint pains, but generally no tissue and cartilage changes seen on X-ray
• One of a group of related diseases (CAPS = cryopyrin associated periodic syndrome)
• This constellation of diseases is being treated with the anti-IL-1 therapeutics

Question 56

Neutropenia

Answer 56

• Low neutrophils counts make people very susceptible to infection (go back to Innate Immunity notes); chemo/radiation therapy often lead to neutropenia
• Chemotherapy reduces number of neutrophils in the bone marrow
• By giving colony stimulating factor, drive neutrophil differentiation
o G-CSF
o Can increase number of neutrophils in the body
• Effects of rG-CSF on mature neutrophils
o Increased function of mature neutrophils in vitro
 Increased chemotaxis
 Enhanced phagocytosis
 Increased cytotoxic killing
 Improved responsiveness to antigens
o Give neutropenic people G-CSF to increase production of PMNs from bone marrow; also activates them

Question 57

Reye’s Syndrome

Answer 57

• A rare illness characterized by hepatic encephalopathy and steatosis that develops from a virus-host reaction in a susceptible patient possibly as a result of exposure to ASA and other NSAID’s (not acetaminophen)
• Encephalopathy - brain swelling causing death
• Steatosis
• No NSAIDS given to children, only take acetaminophen

Question 58

GI effects of NSAIDS

Answer 58

• Aspirin is hard on GI gastric mucosa – gastric mucosa is stimulated to be produced by prostacyclin
o Gives protective coating over the villus
o Without it will increase the acid concentration and will cause ulcer
• Inhibition of COX-1 (↓ E2, I2)
• ↑ H+
• ↓ mucopolysaccharide protectant
• ↓ platelet aggregation
• GI irritation
• Exacerbation of ulcers
• Loss of blood

Question 59

SCARS – severe cutaneous adverse reactions

Answer 59

• Allergic reaction to NSAIDs
• SCARs may cause permanent sequelae such as disfigurement, blindness and death.
• Importantly, these reactions may occur without warning.
• The overall risk of SCARs associated with the use of NSAIDs is extremely low
• The highest reported incidence is with celecoxib at six cases per 1 million person-years

Question 60

Stevens Johnson syndrome

Answer 60

• Life threatening skin condition similar to TEN (toxic epidermal necrolysis), both under the category of SCAR
• Cell death causes the epidermis to separate from the dermis.
o Entire body blisters and causes epidermis to separate from dermis
• Common sites of lesions are in mucosal membranes.
• Only known cause is medications

Question 61

Aspirin toxicity

Answer 61

•	Low concentration 
o	Analgesic, antipyretic, antiplatelet effects 
o	Gastric intolerance, bleeding 
o	Hypersensitivity reactions 
o	Impaired homeostasis 
•	Higher concentration 
o	Anti-inflammatory 
o	Uricosuric 
•	At edge of toxicity will have tinnitus 
o	Sign of aspirin toxicity 
•	As increase in concentration will have more adverse effects 
o	Central hyperventilation 
o	Fever, dehydration metabolic acidosis 
o	Renal and respiratory failure 
•	Salicylism
o	Tinnitus (>25 mg/dL)
o	GI upset
o	Hyperventilation
o	Can kill yourself with aspirin

Question 62

Mechanism of toxicity in acetaminophen

Answer 62

• Mediated by a metabolite created in the liver called NAPQI – N-acetyl-p-benzoquinone imine
• Conversion is via multiple p450 enzymes, a very large family of enzymes, many of which are involved in drug metabolism
o Individual genetic variations, will make some people more or less susceptible to liver toxicity
• Initial damage can either be repaired or accelerated depending on the balance of pro- versus anti-inflammatory cytokines
• Alcohol abuse can tip the balance, as can genetics
• Normally by glucuronyl transferases and sulfotransferases acetaminophen is converted to stable metabolites and will be excreted by kidney
• If too much acetaminophen, the enzymes can be overwhelmed
• The excess will be shunted over to the CYP450 pathway and make metabolite – NAPQI
• Metabolite can be converted back to stable form is sufficient N-acetylcysteine
o Through glutathione transferase the NAPQI will be made into stable metabolites for excretion
o N-acetyl cysteine is used clinically when suspecting overdoses
• Bound metabolite to hepatocyte activate the macrophages
o Inflammatory cytokines attracted to site
• If the T cell expresses CD44 will have hepatocyte recovery
o Recovery because the T cell will find the dead cells and phagocytosis and will go back to health
• If the T cell does not express the CD4 receptor, cells will die
o Spreading of apoptosis throughout the hepatocytes
• If have a genetic predisposition toward reduced CD44 expression it can increase the risk toxicity

Question 63

Chron’s Disease

Answer 63

• A type of inflammatory bowel disease – thought to be autoimmune
• Affects many parts of the intestine
• Combined genetic and environmental origins
• No cure, try to control symptoms, maintain remission, prevent relapse
• Treating Crohn;s
o Prednisone is the “workhorse” of Crohn’s treatments, used with patients that don’t respond to antibiotics or 5-ASA agents, which most don’t
o It immediately and powerfully suppresses symptoms, but also causes side effects, some severe
o DMARD’s are used in extreme cases.

Question 64

Systemic lupus erythematosus (SLE)

Answer 64

• Thought to be an autoimmune disease
• Attacks the joints, organs and skin, but highly variable between individuals
o Can be difficult to diagnosis
o Something only internal, other times only external
• 4 times more frequent in women.
o Most autoimmune diseases are more common in females
• Classic “butterfly” rash.
• Treating lupus
o Treated with NSAIDs in milder cases and during remission
o Steroids are most common treatment during flares.
o For both this and Crohn’s Prednisone offers almost immediate relief

Question 65

Anaphylaxis

Answer 65

• Anaphylaxis - an extreme systemic form of immediate hypersensitivity in which the mediators released by mast cells or basophils cause bronchial constriction, massive tissue edema and cardiovascular collapse;
• Anaphylactic shock - cardiovascular collapse (a fall in blood pressure or shock) that occurs in the setting of a systemic immediate hypersensitivity reaction.
• Anaphylactic shock
• An extreme systemic form of immediate hypersensitivity reaction
• Mast cells and basophils release inflammatory mediators that cause:
o Bronchial constriction
o Massive tissue edema
o Cardiovascular collapse
• Epinephrine is the primary therapy
o Epinephrine restores cardiac output and blood pressure
• Anaphylatoxins in complements
o C3a, C4a, C5a
o When complement components are excessively activated can cause anaphylaxis
o Activate mediator release by mast cells
o Induce smooth muscle contraction
o Increase vascular permeability
o Widespread degranulation can cause a shock-like syndrome

Question 66

Bronchial Asthma

Answer 66

• Asthma is an inflammatory disease usually caused by repeated immediate hypersensitivity reactions in the lung, leading to the triad of :
o Intermittent and reversible airway obstruction
o Chronic bronchial inflammation with eosinophils
o Bronchial smooth muscle cell hypertrophy and hyperreactivity
• Histopathological features of bronchial asthma
o Chronic bronchial asthma – filled with mucus an inflammatory infiltrates
• Bronchial asthma: mediators and treatment
o Cromolyn stabilize mast cells so granules are not released
o Steroids stabilize mast cell and stop the release of biogenic amines, TNF, IL-4, IL-5 and other cytokines
o Antagonists of leukotriene can restrict bronchial constriction
o Epinephrine and theophylline allow for bronchial relaxation
o All symptoms are attributed to mediators produced by mast cells and basophils

Question 67

Treatment of immediate hypersensitivity reactions

Answer 67

• Anaphylaxis
o Therapy – epinephrine
o Mechanism of action – causes vascular smooth muscle contraction and increases cardiac output (to counter shock), relaxes airway muscle, inhibits mast cell degranulation
• Bronchial asthma
o Corticosteroids – reduce inflammation
o Leukotriene antagonists – relax bronchial smooth muscle and reduce inflammation
o Phosphodiesterase inhibitors – relax bronchial smooth muscle
• Various allergic diseases
o Desensitization (repeated administration of low disease of allergens) – may inhibit IgE production and may increase production of other Ig isotypes, may induce T cell tolerance
o Anti IgE antibody – neutralize and eliminate IgE
o Antihistamines – block actions of histamine on vessels and smooth muscles
o Cromolyn – inhibits mast cell degranulation
• Desensitization
o If you want to get rid of excessive IgE need to have immunological intervention
o Subcutaneous or sublingual route
o If know allergic to certain allergen, small doses introduce the allergen at spaced interval
o Slowly introducing allergen into the system, over time the person will make IgG antibodies to the allergen instead of IgE
• Antigen-antibody complexes can shut down B cells so they don’t make antibodies
• Antihistamines block the actions of histamine on blood vessels and smooth muscles
• Sodium cromolyn inhibits mast cell degranulation
• Humanized anti-IgE monoclonal antibody (e.g., Omalizumab, IgG1k) is a recently approved therapy for reducing serum IgE levels in certain patients with specific allergies
o This antibody binds to free IgE on an epitope that binds to FcεRI and thereby prevents the IgE to bind to its receptor.
o It also can stabilize the mast cells and basophils by downregulating the surface FcεRI expression

Question 68

Treatment of chronic hypersensitivity diseases

Answer 68

• Use of agents (e.g., corticosteroids) that limit inflammation and its damaging consequences
• Plasmapheresis helps to reduce the levels of circulating disease-causing antibodies and immune complexes in severe cases.
• Intravenous IgG (IVIG):
o May suppress antibody production by inducing the expression of inhibitory FcγRIIB and binding to it
o May bind to IgE via anti-idiotypic antibodies and facilitate their removal from the body
o May reduce IL-4
o Up-regulate and bind to inhibitory receptor, shut down B cells
• Immunotherapeutic approaches under clinical trials:
o The blockade of CD40L to inhibit T cell dependent B cell activation.
 CD40L blockade permits inhibition of Th2 subset
o Tolerance induction to allergens.
o Control of antibody production via depletion of B cells by anti-CD20 antibody.
o Induction of regulatory T cells
 Th2 cells needed for class switch of IgM into IgE induced by IL-4

Question 69

Type II Hypersensitivity - human antibody-mediated diseases

Answer 69

• Autoimmune hemolytic anemia
o Target antigen – erythrocyte membrane proteins (Rh blood group antigens, I antigen)
o Mechanisms of disease – opsonization and phagocytosis of erythrocytes
o Clinical manifestations – hemolysis, anemia
 Patient is anemic because hemolysis
• Autoimmune thrombocytopenia purpura
o Target antigen – platelet membrane proteins (gpIIb, IIIa integrin)
o Mechanism of disease – opsonization and phagocytosis of platelets
o Clinical manifestations – bleeding
• Good pasture’s syndrome
o Target antigen – non-collagenous protein in basement membranes of kidney glomeruli and lung alveoli
o Mechanisms of disease – complement and Fc receptor mediated inflammation
o Clinical manifestations – nephritis, lung hemorrhage
• Graves’ disease
o Hyperthyroidism
o Target antigen – TSH receptor
o Mechanisms of disease- anti-body mediated stimulation of TSH receptors
o Clinical manifestations – hyperthyroidism
• Myasthenia gravis
o Target antigen – acetylcholine receptor
o Mechanisms of disease – antibody inhibits Ach binding, down modulates receptors
o Clinical manifestations – muscle weakness, paralysis
• Pemphigus vulgaris
o Target antigen – proteins in intercellular junctions of epidermal cells (epidermal cadherin)
o Mechanisms of disease – antibody-mediated activation of proteases, disruption of intercellular adhesions
o Clinical manifestations – skin vesicle (bullae)
• Pernicious anemia
o Target antigen – intrinsic factor of gastric parietal cells
o Mechanisms of disease – neutralization of intrinsic factor, decreased absorption of vitamin B12
o Clinical manifestations – abnormal erythropoiesis, anemia
• Rheumatic fever
o Target antigen – streptococcal cell wall antigen, antibody cross reacts with myocardial antigen
o Mechanisms of disease – inflammation, macrophage activation
o Clinical manifestations – myocarditis, arthritis

Question 70

Type III hypersensitivity immune complex diseases

Answer 70

• SLE (systemic lupus erythematosus)
o Antibody specific – DNA, nuceloproteins, others
o Clinical manifestations – nephritis, arthritis, vasculitis
• Polyarteritis nodosa
o Antibody specific – often microbial antigens (e.g. hepatitis B virus surface antigen)
o Clinical manifestations – vasculitis
• Post-sterptococcal glomerulonephritis
o Antibody specific – streptococcal cell wall antigens
o Clinical manifestations – nephritis
• Serum sickness
o Antibody specific – various protein antigens
o Clinical manifestations – systemic vasculitis, nephritis, arthritis
• Arthus reaction (experimental)
o Antibody specific – various protein antigens
o Clinical manifestations – cutaneous vasulitis
• In the diseases, immune complexes are detected in the blood or in the tissues that are the sites of injury
• In all the disorders, injury is caused by complement-mediated and Fc receptor-mediated inflammation.

Question 71

Tuberculosis

Answer 71

T cell mediated
o Opaque areas caused by fibrosis of lung due to pulmonary TB
o TB bacterium likes apexes of lungs – upper parts of lungs because of oxygenation patterns
o Fibrous tissues caused by healing of granulomas
o Center of TB becomes jelly like – caseous necrosis
o Tissue damage can be caused by chronic granulomatous inflammation

Question 72

Leprosy (by M. leprae)

Answer 72

T cell mediated
o Lepromatous leprosy - lesions all over the body
o Tuberculoid leprosy - Not as diffuse, not more than one or two lesions
o Tuberculoid is making more Th1 cytokines
 IL-2, IFN-gamma, TNF-beta
o Lepromatous making more Th2 cytokines
 IL-4, IL-5, IL-10
o Same bacteria causing two different diseases – making different cytokines
o TNF and IFN are important to make good granulomas
o If you cannot make good Th1 cells cannot make good granulomas
 Lepromatous cannot make good Th1, cannot make good granulomas, - lesions will spread throughout the body
 Tuberculoid can make good granulomas because can make Th1 and therefore have very isolated lesions

Question 73

Leishmaniasis (by Leishmania)

Answer 73

T cell mediated
B6, BALBc strains of mice
o The one strain that does not develop disease makes Th1
o Other mouse that is seriously infected makes Th2
 Will have disseminated infections

Question 74

T1DM

Answer 74

T cell mediated, autoimmune
 Target antigens: Insulin, glutamic acid decarboxylase-65 (GAD65), etc
 Immune response against self-antigen causes DTH

Question 75

MS

Answer 75

T cell mediated, autoimmune
 Self-antigens involved: myelin basic protein, proteolipid protein, etc
 The plaques of demyelination appear as well-demarcated pale areas with a central blood vessel

Question 76

Wegener’s Granulomatosis

Answer 76

T cell mediated
o Vascular – not sure how much of the role is autoimmunity
o Rare types of vasculitis in the blood vessel will see granulomas

Question 77

Contact hypersensitivity

Answer 77

• Both DTH and CD8+ CTL responses are involved in Contact hypersensitivity (e.g., to Poison ivy, Nickel) and Graft rejection
o Poison Ivy
o Nickel reaction
o In contact sensitivity, both the DTH and the CTL response may participate in tissue damage, and their relative contribution may vary depending on the antigen

Question 78

Superantigen mediated disease

Answer 78

T cell mediated
o Prototypic superantigens are present in Staphylococcus aureus and Streptococcus pyogenes
o Superantigens bind to class II and to the TCR framework regions, thus bridging the antigen receptor and the MHC molecule.
o This TCR/MHC interaction is peptide non-specific, but can result in general T cell activation (at least for any T cell bearing the particularV)
o Massive T cell activation and cytokine storm

Question 79

Primary immunodeficiency

Answer 79

o	Hereditary 
	Born with immunodeficiency
	Genetic defect 
o	Due to genetic defects in the  production, maturation, or function of
	B cells
	T cells
	Severe Combined Immune Deficiencies (SCID) – T + B defects
	Phagocytes
	Complement

Question 80

Secondary immunodeficiency

Answer 80

o Acquired
 Born immunocompetent but when through various exposures the patient becomes immunodeficient
o Due to infections (e.g. AIDS), malnutrition, burns, ionizing radiation, immunosuppressive drugs (e.g. cortico-steroids, cytostatics), stress, alcohol, various other illnesses in a previously normal person

Question 81

Clinical manifestations of immunodeficiency

Answer 81

• Increased susceptibility to infection:
o Humoral defects (B cell deficiency) - bacterial, viral, parasitic
o Cell mediated immunity (T cell deficiency) - viral, parasitic, fungal, intracellular microbes
• Increased incidence of autoimmunity and malignancy
• Treatment: antibiotics, IgG injections, bone marrow or fetal thymus transplantation, gene therapy

Question 82

When to suspect immunodeficiency

Answer 82

• Primary will be in children
• >10 episodes of otitis media per year
• >2 episodes of consolidated pneumonia per year
• >2 life-threatening infections such as meningitis, sepsis
• >2 serious sinus infections in one year
• Recurrent abscesses
• Autoimmunity in children
• Dysmorphic features with recurrent infections
• Infections with unusual organism (fungi [Aspergillus, Candida], Pneumocystis carinii), e.g. oral thrush
o Infections with commensals

Question 83

Thrush

Answer 83

• Oral thrush = oral candidiasis
o Candida develops in the mouth
• Thrush - A contagious disease caused by a fungus, Candida albicans, that occurs most often in infants and children
• Characterized by small whitish eruptions on the mouth, throat, and tongue, and usually accompanied by fever, colic, and diarrhea
• Normally limited to neonates, infants, or adults on antibiotics of steroids.
• If recurrent after infancy with no antibiotics or steroid therapy, consider immunodeficiency

Question 84

Classification of primary immunodeficiency disorders

Answer 84

• Antibody defects (B cell) - abnormal B cell development and function in the presence of essentially normal T cell development
• T cell abnormalities with variable B cell defects
• Severe Combined Immunodeficiencies (SCID) – combined B + T cell defects
• Phagocytic Defects
• Complement Deficiencies
• Immunodeficiency associated with other defects

Question 85

Antibody immunodeficiency disorders

Answer 85

• Clinical presentation
o Infections with high-grade extracellular encapsulated pathogens (Staph, Strep, Hemophilus, pneumococcus) and chronic sinusitis, bronchitis, or pneumonia is common
 Bacteria such as Staph and Strep are relatively resistant to phagocytosis by macrophage and neutrophil
 Bacteria-specific antibody is necessary to allow opsonization.
o Paucity of lymphoid tissue if acquired early in life.
o Compatible with nearly normal growth and survival into adulthood.
o Autoimmune diseases occur with increased frequency.
• Treatment - antibody replacement with pooled gamma globulin injections.
• Examples
o Transient hypoglobulinemia of infancy
o Common variable immunodeficiency (CVID)
o Bruton’s agammaglobulinemia (aka X linked agammaglobulinemia – XLA)
o IgA deficiency
o X-linked lymphorpoliferative syndrome (Duncan’s Syndrome)

Question 86

Transient Hypoglobulinemia of Infancy

Answer 86

• Hypo – low
• Globulin – globulin in blood - low IgG, low IgM, low IgA in blood
• Transient – was no there, came, and will go away
• As maternal IgG levels in the infant decline (age 3 – 6 month), some infants fail to produce adequate amounts of IgG.
• Regulation does not happen well enough in these cases
o Will develop infections, diarrhea – but not severe
• Transient – the kid will pick up the production of regulation
• Infections may not be severe
• IV immunoglobulin is unnecessary
• Deficiency spontaneously resolves in 1st to 2nd year of life.
• If does not resolve – consider possible Bruton’s agammaglobulinemia or class/subclass deficiency.

Question 87

Common Variable Immunodeficiency (CVID)

Answer 87

• The most prevalent primary immunodeficiency
• Heterogeneous, can be sporadic or familial syndrome
• Manifests at any time from infancy to after 40 y.o. (peaks of onset in children aged 1-5 years and in persons aged 16-20 years).
• Normal to low peripheral B cells, but absence of plasma cells
• Variable low IgG, IgM, IgA
• Recurrent bacterial, viral, parasitic infections; increased incidence of autoimmune disease and malignancy
o Increased infections.
o Pyogenic infections, sometimes associated with autoimmunity (pernicious anemia, hemolytic anemia, rheumatoid arthritis) and malignancies (especially in children)
• Various etiology - B cell defects, deficient T cell help, or excessive suppressor T cell activity; often unknown
• Treatment - Ig replacement therapy or bone marrow transplant
• If the exam question describes vague mild immunodeficiency symptoms, the answer is likely CVID

Question 88

Bruton’s agammaglobulinemia, or X-linked agammaglobulinemia (XLA)

Answer 88

• Immunoglobulins are completely gone, no production of immunoglobulin
• Among the more common primary immunodeficiency’s; only boys are affected (X-linked gene)
• Bruton’s tyrosine kinase (BTK) gene defect
o If mutated the entire B pathway is blocked
o T cells are normal, no B lymphocytes
• In the absence of BTK, B lymphocytes do not differentiate or mature.
• Without mature B lymphocytes, antibody-producing plasma cells are also absent but T cells are normal.
• Recurrent pneumonias and other bacterial sinopulmonary infections, sepsis, meningitis, and diarrhea
• Autoimmunity is common (RA-like illness)

Question 89

IgA Deficiency

Answer 89

• A very common congenital immunodeficiency (1 in 600-700); many patients unaware that they have this disease.
• Autosomal inheritance
• Serum IgA is low, IgM and IgG levels are normal
o Never seen IgA – will be foreign protein to them
• Clinically may be normal or may have pulmonary and gastrointestinal infections
• Autoimmune diseases
• May react to IgA in transfusions (it is a non-self protein to these patients), so need to avoid the infusion of serum
o Immunized them to IgA with the first transfusion
o When giving IgA the second time will react against foreign IgA
o IgA deficiency caused the patient to die
• If an exam question describes a mild immunodeficiency with pulmonary and gastrointestinal symptoms, the answer is likely IgA deficiency

Question 90

X-linked Lymphoproliferative Syndrome (Duncan’s disease)

Answer 90

• Mutation in the SH2D1A gene encoding SAP protein
• Rare defect in the immune response to Epstein-Barr Virus (EBV)
o Normally EBV infects us but body can deal with it
o Some develop infectious mononucleosis
o EBV infects B cells and B cells proliferate uncontrollably
• Leads to severe, often deadly, infectious mononucleosis (~50%), B cell lymphomas (~25%), hypogammaglobulinemia (~30%)
• Fail to make anti-EBV Ab, defective cytokine production, low CD4/CD8 ratio
• Defect is the molecules of a signaling cascade that regulates development and activation of T cells and NKT cells.
• Production of cytokines by CD4+ T cells, NK cell-mediated cytotoxicity; and B cell antibody production are all impaired

Question 91

Primary T cell-mediated deficiencies

Answer 91

• Defects in T cell maturation and activation
• Mutations – e.g., absence of T cell receptor chains (CD3 epsilon or gamma chains), ZAP-70, reduced gamma-interferon or IL-2 production, or lack of cytokine receptors
• Examples
o DiGeorge’s Syndrome
o Chronic Mucocutaneous Candidiasis
o Hyper IgM syndrome

Question 92

DiGeorge’s Syndrome (Thymic Hypoplasia)

Answer 92

• Sporadic disturbed development of the 3rd and 4th pharyngeal pouches before the 8th week of gestation – deletion in 22 chromosome or non-genetic (teratogens)
• Defect in T cell maturation
• Defective development of the thymus (defective T cell maturation) parathyroid glands (hypocalcemia, which causes tetany), great vessels (congenital defects) and face, and esophagus (esophageal atresia)
• Susceptible to mycobacterial, viral, and fungal infections
• Partial or complete loss of:
o The thymus - absent or reduced T cells; mycobacterial, viral, fungal infections (severity depends on the degree of defect).
 Thymic hyperplasia or aplasia
 No T cells, low CD4
 No orchestration of B cells by CD4, severe immunodeficiency in these patients
o Parathyroids - tetany due to hypocalcaemia
 Tetany is important clue – all of the muscles are contracted
o Thyroid – hypothyroidism
o Also craniofacial defects:
 Micrognathia (abnormally small jaws, esp. the mandible),
 Hypertelorism (abnormal distance between two paired organs),
 Abnormal external ears
 Cardiovascular defects (heart and great vessels)
 Esophageal atresia:
 Cognitive, behavioral, and psychiatric problems
• Treat with fetal thymic transplant
• For the exam: immunodeficiency combined with tetany, and/or hypothyroidism, and/or craniofacial defects, and/or major cardiovascular dysgenesis

Question 93

Chronic Mucocutaneous Candidiasis (CMC)

Answer 93

• Candida is involved – covers skin, scalp, nails
o T cell dysfunction
• T cell dysfunction specifically against a yeast-like fungus Candida albicans due to various molecular defects
• Usually presents in infancy or early childhood, with a mean onset at 3 years, but adult onset also reported
• Candidal infection of skin, nails, and/or mucous membranes.
• Heterogeneous group of conditions, but IL-17 and IL-17R deficiencies cause CMC
• Persistent Candida infections of scalp, nails, mucous membranes

Question 94

X-linked Hyper IgM

Answer 94

o Only males will have it – CD40 L is encoded on X chromosome
o Failure of immunoglobulin isotype switching due to mutation of CD40L gene on X chromosome – boys only
o Deficiency of all Ig classes while excess IgM due to failure to switch
o Primary T cell defect manifesting as antibody deficiency
o Germinal centers do NOT form
 There will be no germinal centers
o The apparent change is in immunoglobulins – high IgM levels, low levels of all other classes of Ig
 However, the true defect is in T cells – defective CD40L

Question 95

Activation-induced cytidine deaminase (AID) deficiency

Answer 95

o Cells receive signal, go into germinal center and cannot complete the job
o Germinal centers will be huge but will never complete the job
o Autosomal recessive – boys and girls
o Recurrent bacterial sino-respiratory and gastro-intestinal
tract infections
o Lymphoid hyperplasia
o Massive germinal centers

Question 96

SCID clinical presentation

Answer 96

o Recurrent bacterial, viral (large DNA viruses), fungal and protozoal infections.
 Candida infections of mucocutaneous surfaces may be initial presentation, followed by intractable diarrhea and pneumonia, especially with opportunistic infections such as Pneumocystis jerovecii.
 Neonatal rash may be graft (maternal T cells) versus host (infant) disease.
o Within the first several months of life, growth and development may be normal initially, but soon growth retardation and failure to thrive are evident, then early death.
 May develop graft versus host disease after transfusions or fatal infections with vaccinations with live organisms.
 About half are inherited in an autosomal recessive manner.

Question 97

SCID – ADA (adenosine deaminase) deficiency

Answer 97

o Autosomal recessive; accumulation of metabolites that are toxic to T and B cells; reduced T and B cell numbers
o Pneumonia, chronic diarrhea, skin rashes
o Get reduction in T and B cell numbers within first year of life.
o Pseudochondrodysplasia-defect in cartilage formation
 Problems with cartilage, because ADA is involved in cartilage formation

Question 98

SCID – PNP (purine nucleoside phosphorylase) deficiency

Answer 98

o Autosomal recessive; accumulation of metabolites that are toxic to T but not B cells - reduced T and normal B cell numbers;
o Ig levels are normal but function impaired
o Toxic products are more toxic to T cells
o B cells are normal, T helper cells are not there – B cells will not be functioning without T cells

Question 99

SCID – Reticular dysgenesis (mitochondrial adenylate kinase 2 deficiency)

Answer 99

o T, B cells, granulocytes virtually absent; the most severe SCID
o Patients rarely survive more than a few days, and are commonly still-born
o Very upstream – above ADA

Question 100

X linked SCID – ”Bubble Boy Disease”

Answer 100

o Lack the common gamma chain (γc) which is shared by the IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 receptors
o Reduced T cell numbers; B cell numbers are not reduced
o Serum IgG is reduced
o Mutations in common gene encoding cytokine receptor gamma chain, which is involved in cytokine signaling, including IL-7 signaling (which promotes lymphocyte maturation) and IL-15 signaling (which is important in natural killer cell maturation).

Question 101

Other causes of SCID

Answer 101

o Bare Lymphocyte Syndrome-Deficient in either MHC Class I or II expression.
 For example, no MHC II → no CD4+ helper T cells → no cytokines regulation of the immune system → SCID.
o SCID with MHC deficiency
 Class II deficiency = bare lymphocyte syndrome, mutations in genes encoding transcription factors essential for class II expression, which leads to failure of antigen presentation to CD4 cells.
 Class I deficiency - decreased CD8 T cells, in some cases caused by mutations in the TAP1 or TAP2 subunit of the TAP (transporter associated with antigen processing).
o JAK-3 mutations – few T cells, normal B cell not receiving help from T cells
o When T helpers are not present will have SCID
o Defects in T cell activation includes mutations in the CD3 epsilon or gamma chains, mutations in ZAP-70, reduced synthesis in IL-2 or IFN-gamma because of defects in transcription factors, lack or IL-2 receptors.

Question 102

Omenn syndrome

Answer 102

o Autosomal-recessive defect of Rag1 or Rag2 or ARTEMIS
 Theses enzymes are necessary for V(D)J recombination
o Mutations that impair but do not completely abrogate their function (minimal residual functioning preserved)
 The enzyme is not complete dead, the mutation is such that the enzyme is not completely off – it is incapacitated but works a little bit
 Some B and T cells are produced but just in small amounts
 Because too few of them there is no regulation – become hyper activated and start attacking the host
o A form of SCID with
 Oligoclonal autoreactive T lymphocytes present produce IL-4 and IL-5
 B cells virtually absent but IgE and eosinophils elevated (do NOT confuse with Job syndrome)
• IL-4 encourages IgE class switch
 The autoimmune aspect manifests as GVHD, combined with SCID and Th2 activation:
• Diffuse erythroderma with skin desquamation and alopecia
• Multiple lymph node enlargement
• Hepatospleno-megaly
• Chronic diarrhea
• Growth retardation
• Recurring fungal and viral infections
• Graft versus host disease – manifests as red skin, skin peeling, alopecia
 Allogeneic bone marrow transplantation is the treatment of choice

Question 103

Radiosensitive SCID

Answer 103

o Artemis is also important―in concert with ATM ―for DNA damage repair; Artemis deficiency = radiosensitive Omenn
 Artemis participates in VDJ and also repairs DNA defects
 Constantly subjected to background radiation – breaks DNA over time
 Artemis and ATM are important for repairing DNA
• Will fix the DNA
 These children cannot have DNA fixes
 If you have Artermis defect will have Omenn Syndrome and will be radio-sensitive – you cannot X ray them

Question 104

Job Syndrome

Answer 104

• Not a SCID but a rare autosomal dominant mutation in STAT3
• Hyper IgE, patient is covered with large pustules
• Recurrent sinopulmonary infections, skin infections, deep sub-cutaneous abscesses
• Most infections due to S. aureus.
• Very high levels of IgE – also called “hyperimmunoglobulinemia E syndrome”
• Coarse facies, retained primary teeth, noneruption of permanent teeth, double rows of teeth with both primary and permanent intermixed teeth
o STAT 3 not only participates in immune signaling also involved in facial structure
o Permanent teeth do not erupt
o STAT3 involved in forming skeletal features in jaw and face

Question 105

Wiskott-Aldrich syndrome

Answer 105

(immunodeficiency, thrombocytopenia, eczema)
• X-linked recessive (affects only boys) genetic defect in a protein called Wiskott-Aldrich syndrome protein (WASp)
o Affects cytoskeleton of lypmphocytes and platelets
• The gene is on the X chromosome; expression limited to cells of hematopoetic origin.
• The protein normally regulates actin cytoskeleton of lymphocytes and platelets; participates in cell growth, endocytosis, exocytosis, and cytokinesis.
o Because platelets are affected will be easy bruising
• Remember the triad: immunodeficiency – thrombocytopenia – eczema, plus WASp.
o X-linked, eczema, thrombocytopenia (reduces platelets), and increased infections.
• A mutation in a single multifunctional gene causes a spectrum of symptoms – a syndrome
• Always a T-cell deficit, often also a B-cell deficit; poor response to polysaccharide antigens – susceptible to polysaccharide-coated bacteria, e.g. Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus.
o Inability to produce antibodies in response to T cell-independent polysaccharide antigens. Infections with encapsulated pyogenic bacteria.
• Often present with petechiae and ecchymoses of the skin and oral mucosa, and bloody diarrhea; recurrent infections (e.g. otitis media); autoimmune disorders (autoimmune hemolytic anemia, arthritis, nephritis)
• Causes of death include recurrent infections (immunodeficiency), bleeding (thrombocytopenia), or malignancy (immunodeficiency).
• Rarely survive beyond childhood.

Question 106

Ataxia-Telangiectasia (A-T)

Answer 106

• Mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage (ATM - ataxia telangiectasia, mutated)
• Autosomal recessive
• Cerebellar atrophy and loss of function leading to uncoordinated (ataxic) movements, choreoathetosis (abnormal body movements), progressive dysarthria (speech defects), characteristic eye movement abnormalities – become wheelchair-bound early in life
• Ocular telangiectasia (dilated blood vessels of the eye), spider angiomas
o Conjunctival vascular telangiectasia in patients with A-T (nasal and temporal interpalpebral conjunctiva).
• Mutation in a single multifunctional gene causes a spectrum of symptoms – a syndrome
• Key features - ataxia, conjuctival vascular telangiectasia, dysarthria (speech defects)
• In addition to ataxia and telangiectasias, the genomic instability in the A-T patients leads to extreme radiosensitivity, sterility, tumors, and immunodeficiency
o Important – because of the radiosensitivity, cannot X-ray these kids
• Effects both T and B cells.
• Decreased or absent IgA leading to recurrent respiratory infections, although severe bacterial or viral opportunistic infections are relatively rare.
• Gamma-globulin injections may be given to help supplement the weakened immune system.

Question 107

Phagocytic defects

Answer 107

• Phagocytes - neutrophils and macrophages
• Bacterial, fungal, viral and protozoal infections
• Skin infections, chronic osteomyelitis (Klebsiella/Serratia)
• Defective killing mechanisms, inability to phagocytose, or reduced numbers of phagocytes.
• Clinical Presentation
o Bacterial and fungal infections, few viral or protozoan infections.
o Prominent skin infections, chronic osteomyelitis draining lymph nodes.
• Defects
o Varied and include intrinsic metabolic defects in enzymes involved in O2-dependent killing mechanisms, as well as intrinsic defects in opsonins and decreased numbers of phagocytes
• Therapy
o Therapeutic and prophylactic antibodies, interferon-gamma, drain
• Examples
o Chronic granulomatous disease
o Chediak-Higashi syndrome
o Leukocyte Adhesion Deficiency (LAD)

Question 108

Chronic Granulomatous Disease

Answer 108

• X-linked defect in phagocytic cells
• Mutations in phagocyte NADPH oxidase system resulting in defective production of superoxide (O2-) and peroxide (H2O2) that are normally involved in killing bacteria (oxidative burst).
o Macrophages and neutrophils produce oxidative burst
o In these patients phagocytes fail to do this
o Accumulate around bug, cannot kill bug will form granuloma
• Leukocytes fail to kill bacteria in vitro.
• Early onset - by 2 to 5 years of age.
• Severe recurrent fungal and bacterial infections, frequently fatal.
• Granulomas in the skin, GI tract, and genitourinary tract
• Defective production of superoxide anion, which is a major microbicidal mechanism in phagocytes
• Defect in innate immunity

Question 109

Chediak-Higashi Syndrome

Answer 109

• Autosomal recessive defect of LYST gene (LYSosomal Trafficking)
o Defect in phagocytes, neutrophils, and macrophages
• Lysosomal defect of phagocytes (neutrophils, macropahges) and other cells; also defect in polymerization of microtubules
• Immunodeficiency: pyogenic infections (strep, staph) affecting respiratory tract, skin
• Abnormal function of platelets: bleeding tendency, easy bruisability
• Oculocutaneous albinism: hypopigmentation of the eyes, skin, and hair
• Progressive neurologic dysfunction
• Infections, albinism, nerve defects, and bleeding disorders due to platelet defects

Question 110

Leukocyte Adhesion Deficiency (LAD)

Answer 110

• Type I: defect in LFA-1/CD18 (beta 2 integrin) – loss of expression on lymphocytes, macrophages, and neutrophils
o Type I: patients succumb to infections commonly before 2 years of age.
• Type II: defect in fucosyltransferase resulting in the loss of the carbohydrate ligand for P-selectin and E-selectin on leukocytes
o Type II: better survival, but have severe growth and mental retardation, and neurological problems
• Leukocytes fail to traffic to sites of infection, leading to infections, poor wound healing.
• Both are rare

Question 111

Monoclonal gammopathies

Answer 111

• Monoclonal gammopathies are relatively rare;
• They may occur at a single site (plasmacytoma) or throughout the bone (multiple myeloma or plasma cell myeloma)
• Ca++ release due to osteoclast activation and bone resorption; other B cells crowded out & actively suppressed.
• Light chain deposits - amyloid - kidney - can cause organ failure
o Overproducing so much of antibody that the light chains dimerize in the absence of heavy chains
o Cause production of amyloid
• Waldenström’s macroglobulinemia
o IgM tumor that causes overproduction of a single IgM molecule
o Punched out lesions in the bones
o Serum has increased calcium – when you have punched out lesion the calcium has to go somewhere
o Single IgM peak
o Waldenström’s - neoplasm of a single clone of B cells (IgM); involves lymph nodes, bone marrow, and spleen.
o Large size of IgM/high concentration in blood - slows blood flow and clogs vessels (hyperviscosity syndrome) - results in confusion

Question 112

Graves Disease

Answer 112

• Nervous, sleepless, unintended weight loss and palpitations
• Diffuse enlargement of thyroid
• Bulging eyes
• In Graves Disease, autoantibodies against the thyroid stimulating hormone (TSH) receptor bind and stimulate the receptor leading to thyroxine release.
• It is associated with a Th2 skew and HLA DR3.
• If you eliminate the thyroid and substitute synthetic thyroid hormone

Question 113

Goodpasture’s Disease

Answer 113

• Type II hypersensitivity
• Autoantibody (IgG) against glomerular basement membrane (collagen type IV) reacts with glomerular and alveolar basement membrane
• Anti-glomerular basement membrane (GBM) disease
• Cross-reacting antigen in kidney & lung tissue: Type IV alpha 3 collagen
o Antigen is specific on basement of lung and kidney
o Type IV alpha 3 collagen
o Autoantibody against specific antigen will have lung hemorrhage – lungs filled will blood
 Antibodies react with antigen on lung membrane and destroy the tissue
• Glomerulonephritis
• Pulmonary hemorrhage
• Bloody urine, decreased urine output, cough with bloody sputum, nonspecific chest pain.
• Smooth linear pattern in immunofluorescence - linear, smooth distribution of the antibody

Question 114

Histology of Goodpasture’s Disease

Answer 114

• The result in the kidney is a proliferative, usually rapidly progressive glomerulonephritis, characterized by “crescents”, whereas in the lung the result is pulmonary hemorrhage.
• Pulmonary hemorrhage
• In the lung the resulting pathology is necrotizing hemorrhagic peumonitis.
• Note the hemorrhage and the numerous hemosiderin laden macrophages
• Severe necrotizing glomerulonephritis
• Crescents: sign of severity
o Look like half-moon in cross section
o Sign of severity
o Any bad disease of kidney can cause this but Goodpasture has this characteristically a lot of them
• In the kidney the Goodpasture (anti-GBM) disease is expressed by severe necrotizing glomerulonephritis with crescents
• Linear indirect immunofluorescence pattern (antigen = Type IV alpha 3 collagen).
• Pulmonary hemorrhage.
• Severe glomerulonephritis with crescents
• Immunofluorescence
o Antigen is distributed regularly on membrane, antibodies will go to these antigen
o Result will be linear immunofluorescence, regularly deposited antigen against the collagen
o In contrast to SLE, where the Antibody-Antigen complexes come from the blood and are therefore haphazardly deposited, in Goodpasture disease the antigen is homogeneously distributed within the glomerular basement membrane (GBM), leading to an equally homogeneous antibody and complement distribution.
o This pattern leads to linear immunofluorescence
o Linear indirect immunofluorescence pattern (antigen = Type IV alpha 3 collagen)
o The IF is linear due to the continuous/regular distribution of the antigen sites in the basement membranes
o Type II hypersensitivity – organ specific

Question 115

Myasthenia gravis

Answer 115

• Type II hypersensitivity – blocking autoantibodies
• Autoantibodies are produced against the Ach receptor
• The antibodies to Ach receptor – the antibodies will be activated complement C1 and complement will make holes in muscle fiber
o Muscle fiber is not completely destroyed, just injures the muscle membrane
o Fine structure of the muscle membrane is injured
• In addition to injuring the membrane structure, the autoantibody cross links the receptor
o The muscle internalizes the receptor and destroys it in response to the cross linking
• Those receptors that remain on surface still have antibody bound – blocking access of Ach to the receptor
• Main injury is delivered by complement – destroys the membrane
o Neuron sends impulse but no contraction
o Patients will feel weak and fatigued
• Ptosis
• Usually in young women, but men, including older men, also affected
• Muscle weakness worsening with muscle use
• Anti-AchR antibody
• Ocular MG develops in many but not all patients with generalized MG: diplopia & ptosis
• ~80% of patients with MG develop thymic hyperplasia and ~15% develop a thymoma
o At risk for thymic hyperplasia and thymoma
• Mechanism of injury – autoantibody driven complement activation

Question 116

Graves disease

Answer 116

• Type II hypersensitivity – stimulating autoantibodies mimicking a physiological ligand
o Patients produce anti-TSH receptor IgG
 Autoantibody mimics Thyroid-stimulating hormone
o Thyroid glands thinks it is activated by TSH
o Produces large thyroid hormone
• Feeds back on pituitary but B cells are not stopped by this mechanism – B cells keep activating the thyroid gland
• Thyroid becomes hyperactive, follicles are enlarged
• Ophtalmopathy: exophthalmos (proptosis) – eyes protrude and feel dry
• Goiter
• Hyperthyroidism: rapidly lose weight without dieting (e.g., 25 lb in a month), hyperactive, irritable, anxious, cannot sleep, tachycardia and arrhythmia, tremor, diarrhea, warm moist skin, heat intolerance
• Usually women, but men also affected
• Target for autoantibodies – TSH receptor
• Result of antibody binding – hyperthyroidism
• Appearance of thyroid – goiter
• Treatment – anti-thyroid drugs
• Clinical phenotype
o Jitteriness, shaking, increased nervousness, irritability
o Rapid heartbeat or palpitations
o Feeling hot
o Weight loss
o Fatigue, feeling exhausted
o More frequent bowel movements
o Shorter or lighter menstrual periods

Question 117

Histology of Graves Disease

Answer 117

• Important features:
o Hypercellularity
o Papillae
o Scalloped margins of the colloid
• Point of contact between cells and colloid decrease – have involutions that go into colloid to try to withdraw faster
• Because of the fast withdrawal will see scalloping
• Hyperfunction of thyroid gland

Question 118

Hashimoto thyroiditis

Answer 118

• Mix of type II and type IV hypersensitivity
o Autoreactive CD4+ T cells collaborating with autoreactive B cells; macrophage involvement
• Autoantibodies directed at thyroglobulin and thyroid peroxidase – may interfere with iodine uptake and binding by thyroglobulin
o Interfere with production of thyroxin
o Metabolism will decrease
• Autoreactive CD4+ T cells release pro-inflammatory cytokines (e.g. TNF-a), collaborate with thyroid autoantigen-responsive B cells to produce anti-thyroid autoantibodies, recruit and activate Mf, autoreactive CD8 cells, and NK cells (ADCC), which subsequently mediate tissue destruction
o T cells infiltrate the thyroid gland
o Activate phagocytes, CTL and NK which start destroying the thyroid gland
• Inflammation may cause tissue damage by triggering apoptosis in thyrocytes by inducing expression of a ‘death’ receptor (Fas)
• Thyroid gland is destroyed, level of TH is low, metabolism is low
• Target for autoantibodies – thyroglobulin
• Result of antibody binding – hypothyroidism
• Appearance of thyroid – goiter
• Treatment – thyroxine
• Clinical phenotype
o Fatigue or lack of energy
o Weight gain
o Feeling cold
o Dry skin and hair
o Heavy menstrual periods
o Constipation
o Slowed thinking

Question 119

Histology of Hashimoto Thyroiditis

Answer 119

• Thyroid infiltrated by lymphocytes and cell injury
• Colloid is replaced by lymphoid cells
o Tons of lymphocytes including germinal centers
o Activating immune cells to destroy the thyroid gland
• Follicles replaced by auto reactive cells
• Diffuse infiltration of the thyroid by mononuclear inflammatory cells-mostly lymphocytes
• The lymphocytes form often well defined germinal centers
• Glandular atrophy with Hürthle cell changes
o Will have apoptosis – dead cells into the colloid
o What is remaining of the living cells that are injured will undergo Hurthle cell changes
 Become very pink
 Accumulation of granules within the cell cause pink color
• The thyroid follicles appear atrophic and/or lined by cells with abundant eosinophilic, granular cytoplasm (“Hürthle cells”)

Question 120

Scleroderma (systemic sclerosis)

Answer 120

• Mixed type II and Type IV damage in a systemic fashion
• Triad of autoimmunity, small vessel obliteration, fibrosis
• 75% of patients are women. In the US, more affected women are African-American
• Systemic sclerosis – skin
o Scars soak the skin
o Radial furrows surrounding the mouth
o Pinched nose
o Scattered telangiectasia
o Skin is shiny
o Tight, adherent to the underlying structures
• Systemic sclerosis – vascular problems
o Raynaud’s phenomenon
o Vascular response to cold or emotional stimuli in damaged small vessels in the digits - episodic vasospasm - triphasic color change (white - blue - red)
o Expose hands to cold – blood vessels contract and digits become very pale because of contraction
 Painful because no circulation – ischemia
o After some time the blood vessel compensates for contraction and overdialate – blood rushes back
 Will first be red and then with the overcompensation the vessel becomes blue
o Interferes with the metabolism of the tissue
 Tissues dying, healing with scar / ulcers
o Digital ulcers, finger tapering, loss of digital pulp resulting from endothelial damage and fibrosis in scleroderma
• Systemic sclerosis - organ involvement
o Fibrosis also affects the organs
o Pulmonary inflammation, fibrosis, and isolated pulmonary hypertension → decline in lung function → major cause of death
o Gastointestinal – esophageal dysmotility, reflux; similar small bowel involvement
o Peripheral vascular involvement – mostly microvasculature
o Cardiac, Renal, Musculoskeletal, Nervous system
• Autoimmunity-fibrosis link
o Profibrotic cytokines from activated T cells, monocytes and platelets
o PDGF
o TGF-b
o IL-4
o Oncostatin M
o MCP-1
• Autoantibodies in scleroderma
o Antibodies against Topoisomerase I
 Anti-Topoisomerase I (anti-Scl-70) antibody highly specific to scleroderma (rare finding in other diseases)
 Present in ~30% patients, associated with diffuse skin involvement, early visceral involvement, including pulmonary fibrosis, and presence of antinucleolar antibodies
o Antibodies against centromere
 Anti-Centromere antibody is associated with limited skin involvement (usually distal extremities and face)
 Slowly progressive visceral involvement
 CREST variant (subcutaneous calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and teleangiectasia)
• Nucleolar pattern of staining with autoantibody in systemic sclerosis
o Autoantibodies bind to nucleoli
o Own cells stained with own antibodies – only nucleoli, not the whole nuclei is stained

Question 121

Systemic lupus erythematosus (SLE)

Answer 121

• Typical pure Type III disease - damage mediated by circulating immune complexes
o Immune complexes against soluble antigens, circulate precipitate and cause disease
o Excess complexes become deposited in the wall of small blood vessels in the renal glomerulus and in joints.
o This leads to complement fixation, activation of phagocytes, and further damage of the tissue, that releases new portion of the antigens
• Disease manifests in glomerulonephritis, vasculitis, and arthritis
• Malar or butterfly facial rash in SLE
• 90% of patients are women.
• In the US, 75% of affected women are African-American.
• Loss of tolerance to nuclear antigens → anti-nuclear autoantibodies → dysregulation of the immune system → autoimmune response → end organ targeting → arthritis, vasculitis, nephritis, neurological disorders
• Criteria for SLE diagnosis
o 4 out of 11 sufficient
o Malar rash
o Discoid rash
o Photosensitivity
o Oral ulcers
o Arthritis
o Serositis
o Renal disorder
o Neurologic disorder
o Hematoligic disorder
o Anti-nuclear antibody
o Immunologic disorder
• Autoantibodies in SLE
o Antinuclear antibody (ANA): sensitive but not specific
 Antibodies against nucleus
 ANA arise very often in broad spectrum of autoimmune diseases
 Antinuclear – in more than 90% of SLE patients, but may also occur in other autoimmune diseases
o Anti-dsDNA: very specific
 Antibodies against double stranded DNA is very specific for lupus
o Anti-Smith (anti-Sm): very specific
 This is very characteristics of SLE
 Present on RNA-protein complex particles, involving snRNAs U1, U2, U4-U6
 Antibodies to Sm found in 20%-30% of patients with SLE
• Homogenous pattern of nuclear staining in autoantibody in SLE
o Will see homogenous pattern with the whole nucleus stained
o Own cells stained with own antibodies – the whole nuclei stain homogeneously (not only nucleoli, as it was in scleroderma patients).

Question 122

Histology of SLE

Answer 122

• In area between dermis and epidermis – ideal trapping area for the immune complex
• Immune complexes(IC) are deposited in blood vessels, kidneys, connective tissue and skin (dermoepidermal junction)
• SLE Glomerular capillary “Wire Loops”
o Caused by massive subendothelial deposits, and extracapillary proliferation.
• Lupus nephritis
o Trapped underneath the epithelium
o Physical entrapment of immunoglobulins
• Immunofluorescence
o Lumpy bumpy – granular in immunofluorescence
o Type III hypersensitivity
o Distinct granules that reflect discontinuous deposition of immune complex
o In the membranous pattern of SLE nephritis the deposits occupy the entire outline of the glomerular basement membranes
o Irregular (“lumpy-bumpy”) pattern in SLE on immunofluorescence
o Due to precipitation of immune complexes, no autoantibody against basement membrane
o It is not the antibody against basement membrane, antibody against antigens in circulation, form immune complexes and precipitated in the capillaries
• Glomerular will be very hypercellular – will be filled with inflammatory cells
o Deposition of immune complexes will lead to inflammation

Question 123

Examples of T cell mediated autoimmune diseases

Answer 123

• Insulin dependent diabetes
o Destruction of beta cells that produce insulin
o Autoreactive T cells against pancreatic beta antigens, insulin, glutamic acid decarboxylase
o Consequence – beta cell destruction
• RA
o T cells against synovial membrane in joints
o Autoreactive T cells against unknown synovial joint antigen
o Consequence – joint inflammation and destruction
• MS
o T cells attack myelin basic protein in the brain
o Autoreactive T cells against myelin basic protein, proteolipid protein
o Consequence – brain invasion by CD4 T cells, paralysis

Question 124

Rheumatoid arthritis

Answer 124

• Type IV hypersensitivity
• T cells come to synovial membrane, produce cytokines
• Attract macrophages and start destroying the joint – destroy cartilage and bone
• Cartilage and bone is replaced by pannus
• Mediated by IL-1 and TNF-alpha
• Pannus – a mass of fibroblastic, vascular and inflammatory cells, secrete inflammatory cytokines (IL-1, TNF-a) which drive secretion of prostaglandins, proteolytic enzymes, and activation of osteoclasts – bone and cartilage destruction
• Identifying features
o Will have destruction of joints, pannus grows around joints
o Will have rheumatic nodules – especially around elbows
o Rheumatoid factor: anti-IgG (particularly against Fc portion of IgG) in 80% cases
 Autoantibodies against other antibodies
 Can be IgM or IgG attacking Fc fragments of IgG
 Highly indicative of RA if have clinical phenotypes
o Anti-CCP (Cyclic Citrullinated Peptide) antibody – early RA, diagnostic when the rheumatoid factor is negative
 Citrulline – produced normally in body as byproduct of arginine metabolism
 Citrulline does not occur in peptides or proteins – should not be there
 These patients have citrulline in their peptides and develop antibodies against them
o HLA-DR4 association
o Important role of IL-17 (Th17)

Question 125

Histology of Rheumatoid arthritis

Answer 125

• Pannus – a mass of fibroblastic, vascular and inflammatory cells
o Secrete inflammatory cytokines (IL-1, TNF-a) which drive secretion of prostaglandins, proteolytic enzymes, and activation of osteoclasts – bone and cartilage destruction
• The synovium becomes grossly edematous, thickened, and hyperplastic, transforming its smooth contour to one covered by delicate and bulbous fronds
o Villi will be fat and protruding
• “Pannus” is a mass of synovium and underlying stroma, consisting of inflammatory cells, granulation tissue, and fibroblasts, which grows over the articular cartilage and causes its erosion
• Germinal centers
• Infiltrated by lymphocytes, will start invading cartilage and bone
• The inflamed synovium appears markedly hypertrophic with formation of villi.
• The synovial stroma contains dense inflammatory aggregates, consisting of B cells (forming lymphoid follicles), helper T cells, plasma cells and macrophages
• Pannus invading cartilage and bone
• Bone and cartilage destruction by the invading pannus
• Rheumatoid nodule (found in soft tissue)
o Fibrinoid necrosis in center surrounded by inflammatory cells
o Extra-articular manifestation of same process
o Rheumatoid nodule: Central zone of fibrinoid necrosis surrounded by inflammatory cells.
o Rheumatoid nodules display microscopically a central zone of fibrinoid necrosis, surrounded by a prominent rim of epithelioid histiocytes, lymphocytes and plasma cells

Question 126

Molecular mimicry

Answer 126

• Streptococcal infection –rheumatic fever
o Anti-streptococcal antibodies react with myocardial and joint self-antigens
o Rheumatic fever begins with a throat infection, but progressively causes other symptoms, including fever, rashes, and inflammation in various organs, including heart (valves) and joints
o Mitral stenosis or regurgitation
• Herpes Simplex and Myasthenia Gravis
o Ach receptor looks like Herpes simplex
o When you develop herpes simplex have antibody that cross with Ach receptor
o Defective immunity leads to autoimmunity
o T cells and B cells attack and destroy a virus – herpes simplex
o The herpes simplex virus has the same peptide sequence in one area as the Ach receptor
o T cells and B cells now mistake the Ach receptor as the herpes simplex virus
 The body then begins an autoimmune attack on its own Ach receptors