robbins ch. 6 Flashcards
What are the major components of the innate immunity?
- epithelial barrier
- Phagocytic cells (mainly neutrophils and macrophages)
- dendritic cells
- NK cell
- plasma proteins (complement)
what antimicrobial molecule does the epithelium produce?
defensins
Natural killer cells provide early protection against what?
viruses and intracellular bacteria
What circulating proteins of innate immunity coat microbes and promote phagocytosis?
Mannose-binding lectin and C-reactive protein
cellular receptors that recognize pamps and damps are called what?
pattern recognition receptors
TLRs signal by a common pathway that culminates in the activation of what transcription factors?
NF-kappaB and Interferon regulatory factors (IRFs)
When NF-kappaB is activated by a TLR, what happens?
stimulates the synthesis and secretion of cytokines and expression of adhesion molecules, both of which are critical for recruitment and activation of leukocytes
When IRFs are activated by a TLR, what happens?
stimulates the production of antiviral cytokines, type I interferons.
What receptors are cytossolic receptors that recognize a wide variety of substances including products from necrotic cells, ion disturbances, and some microbial products?
Nod-like receptors (NLRs)
The NLRs that signal via the inflammasome actives what enzyme to cleave what?
caspase-1 to cleave and produce active IL-1
IL-1 is a mediator of inflammation that does what?
rectruits leukocytes and induces fever
Gain of function mutations in one of the NLRs results in what?
periodic fever syndromes called autoinflammatory syndromes
Autoinflammatory syndromes respond very well to treatments with what?
IL-1 antagonist
What receptors expressed on the plasma membrane of macrophages and dendritic cells detect fungal glycans and elicit inflammatory reactions to fungi?
C-type lectin receptors (CLRs)
What receptors are located in the cytosol of most cell types and detect nucleic acids of viruses that replicate in the cytoplasm of infected cells?
RIG-like receptors (RLRs)
What do RLRs stimulate the production of?
antiviral cytokines
What do G protein coupled receptos on neutrophils, macrophages, and most other types of leukocytes recognize?
short bacterial peptides containing N-formylmethionyl residues
What does recognition by the G protein receptor on neutrophils cause?
chemotactic responses
What receptors recognize microbial sugars and induce phagocytosis of the microbes?
mannose receptors
What are the 2 main mechanisms of innate immunity?
inflammation and antiviral defense
Type I interferon
Anti-viral
Mature lymphocytes that have not encountered the antigen for which they are specific are said to be what?
naive
After naive cells are activated by recognition of antigens and other signals, they differentiate into what 2 cells?
effector cells and memory cells
The enzyme in developing lymphocytes that mediates recombination of gene segments is the product of what genes?
RAG-1 and RAG-2 (recombination activating genes)
what is the difference between germline antigen receptor genes of T and B cells and other parts of the body?
There are recombined in T and B cells
What is a valuable assay for detecting tumors derived from lymphocytes?
analysis of antigen receptor gene rearrangements
Stucture of a TCR?
a disulfide-linked heterodimer made up of an alpha and beta polypeptide chain each have a variable (antigen binding) region and a constant region
What do the alpha and beta chains of the TCR recognize?
peptide antigens that are presented by MHC molecules on the surface of antigen-presenting cells.
What TCR recognizes peptides, lipids, and small molecules without a requirement for display by MHC proteins?
gamma/delta
what T cells recognize glycolipids that are displayed by the MHC-like molecule CD1?
NK-T cells
What antibodies present on the surface of all mature, naive B cells?
IgM and IgD
What do B cells develop into after stimulation by antigen and other signals?
plasma cells
What are the invariant proteins that are also contained in the B-cell antigen receptor complex?
Ig-alpha (CD79a) and Ig-beta (CD79b)
what do B cells express that recognize complement products generated during innate immune responses?
type 2 complement receptor (CR2 or CD21)
What do B cells express that receives signals from helper T cells?
CD40
What is used by the Epstein-Barr viurs (EBV) as a receptor to enter and infect B cells?
CR2 or CD21
What are the most important antigen-presenting cells for initiating T-cell responses against protein antigens?
Dendritic cells
immature dendritic cells within the epidermis are called what?
langerhans cells
What are the cells that bear Fc receptors for IfG and receptor for C3b and trap antigens bound to antibodies to present to B cells?
follicular dendritic cells
What cells function to destroy irreversibly stressed and abnormal cells such as virus infected cells and tumor cells?
NK cells
What 2 cell surface molecules are commonly used to identify NK cells?
CD16 and CD56
Describe the CD16 on NK cells and what it is used for?
Fc receptor for IgG; gives NK cells the ability to lyse IgG coated target cells. known as antibody-dependent cell-mediated cytotoxicity (ADCC)
What family of receptors is the best characterized ACTIVATING receptors on NK cells?
NKG2D family
What do NK cell inhibitory receptors recognize?
self class I MHC molecules which are expressed on all healthy cells
What do NK cells secrete?
IFN-gamma which activates macrophages
What cytokines regulate NK cells?
IL-2, IL-15, and IL-12
what do IL-2 and IL-15 do to NK cells?
stimulate proliferation
What does IL-12 do to NK cells?
activates killing and secretion of IFN-gamma
The Thymus and Bone marrow are consider what type of organs?
Generative lymphoid organs because T and B lymphocytes mature and become competent to respond to antigens
What are the peripheral lymphoid organs?
- lymph nodes
- spleen
- the mucosal and cutaneous lymphoid tissues
In the morphology of the lymph node, the B cells are located where?
T cells?
Follicles in the Cortex
paracortex adjacent to the follicle
If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called what?
germinal center
In the spleen, T lymphocytes are concentrated where?
B cells?
periarteriolar lymphoid sheaths surrounding small arterioles
follicles
Why do T lymphocytes need to recirculate and B cells can remain in lymphoid organs and the bone marrow?
T cells have to go find the antigens or the infections while B cells secrete antibodies that can be carried by the blood to distant tissues
In humans, the MHC molecules are called what?
human leukocyte antigens (HLA)
The genes encoding HLA molecules are clustered on a small segments of what chromosome
chromosome 6
Where are Class I MHC molecules expressed?
all nucleated cells and platelets
Describe the structure of the class I MHC molecule
heterodimer; polymorphic alpha or heavy chain linked to nonpolymorphic beta-2-microglobulin
The alpha chain of the class I MHC molcule are encoded by what 3 genes?
HLA-A, HLA-B, and HLA-C
the nonplymorphic alpha-3 domain of class I MHC molecules has a binding site for what?
CD8
Class II MHC molecules are encoded in a region called what? which has what 3 subregions?
HLA-D; HLA-DP, HLA-DQ, and HLA-DR
Describe the structure of the class II MHC molecule
heterodimer; polymorphic alpha and beta chains both which have 2 domains.
Where is the peptide binding cleft in the class II MHC molecule?
formed by an interaction of the alpha 1 and beta 1 domains
Class II MHC molecules present what antigens?
those that are internalized into vesicles and are typically derived from extracellular microbes and soluble proteins
what cells express class II MHC molecules?
macrophages, B lymphocytes, and dendritic cells
What are the innate immunity cytokines?
- TNF
- IL-1
- IL-12
- Type 1 IFNs
- IFN-gamma
- chemokines
in adaptive immune responses, cytokines are produced principally by what?
CD4+ T lymphocytes activated by antigen
what are the main cytokines of the adaptive immune system?
- IL-2
- IL-4
- IL-5
- IL-17
- IFN-gamma
What cytokines serve mainly to limit and terminate immune responses?
TGF-beta and IL-10
Some cytokines stimulate hematopoiesis and are called what?
colony-stimulating factors (CSFs)
2 examples of CSFs
GM-CSF and IL-7
Therapy for rheumatoid arthritis?
TNF antagonist
What are the microbial mimics given in an immunization called?
adjuvants
What are the principal costimulators for T cells that are expressed on antigen presenting cells?
B7 proteins (CD80 and CD86)
What on T cells recognize CD80 or CD86?
CD28
what is one of the earliest responses of CD4+ helper T cells?
- secretion of IL-2
- expression of high-affinity receptors for IL-2
what does IL-2 do?
growth factor that act on T lymphocytes and stimulates their proliferation, leading to an increases in the number of antigen-specific lymphocytes
The functions of helper T cells are mediated by what?
CD40L and cytokines
Cells of the Th1 subset secrete what cytokine?
IFN-gamma
What does IFN-gamma from Th1 cells do?
macrophage activation and stimulations of IgG
What cytokines induce the Th1 subset?
IFN-gamma and IL-12
Th1 protects against what?
intracellular microbes
What do Th2 secrete?
IL-4, IL-5, and IL-13
What cytokine induces Th2 subset?
IL-4
What does IL-4 from Th2 do?
B cells to IgE secreting plasma cells
What does IL-5 from Th2 do?
activates eosinophils
What do Th2 protect against?
helminthic parasites
Th2 cells induce what pathway of macrophage activation?
alternative which is associated with tissue repair and fibrosis
Th17 produce what cytokines?
IL-17 and IL-22
What cytokines induce Th17?
TGF-beta, IL-6, IL-1, and IL-23
what does IL-17 from Th17 do?
recruit neutrophils and monocytes
what does Th17 protect against?
extracellular bacteria and fungi
Polysaccharides and lipids stimulate secretion mainly of what antibody?
IgM
Isotype switching is induced by what cytokines?
IFN-gamma and IL-4
Isotype switching and affinity maturation occur mainly where?
germinal centers
Which antibody opsonizes microbes?
IgG
What antibodies activate the complement system by the classical pathway?
IgG and IgM
What antibody is secreted from mucosal epithelia and neutralizes microbes in the lumens of the respiratory and GI tracts?
IgA
What antibody is actively transported across the placenta and protects the newborn until the immune system becomes mature?
IgG
Name the hypersensitivity: immediate, caused by Th2 cells, IgE antibodies and mast cells.
Type 1
Name the hypersenstivity: antibody-mediated, secreted IgG and IgM injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation
Type 2
Name the hypersensitivity: immune complex mediated. IgG and IgM bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation
type 3
Name the hypersensitivity: cell-mediated. sensitized T lymphocytes (Th1, Th17, and CTLs) are the cause of the tissue damage.
Type 4
Type I hypersensitivity reactions are often also called what?
allergy
What are the well defined phases of many local type I hypersensitivity reactions?
Immediate reaction and Late-phase reaction
What chemokines, drugs, and physical stimuli cause secretion of mast cell granules?
- IL-8
- Codeine, morphine, and melittin (bee venom)
- heat, cold, sunlight
How are basophils different from mast cells?
they are not normally present in tissues but rather circulate in the blood in extremely small numbers
What is the high affinity receptor for IgE found on mast cells and basophils?
Fc-epsilon-RI
Preformed mediators contained within mast cell granules are the first to be released and can be divided into what 3 categories?
- Vasoactive amines
- Enzymes
- Proteoglycans
What is the most important mast cell derived amine?
Histamine
What does histamine do?
causes intense smooth muscle contraction, increased vascular permeability, and increased mucus secretion by nasal, bronchial, and gastric glands
What are the preformed enzymes in mast cell granules?
neutral proteases (chymase, tryptase) and several acid hydrolases
What do the preformed enzymes do?
cause tissue damage and lead to the generation of kinins and activated components of complement (C3a) and generate kinins
What are the preformed proteoglycans in mast cell granules?
heparin (anti-coagulant) and chondroitin sulfate
What do the preformed proteoglycans of mast cell granules do?
package and store the amines in the granules
What are the major lipid mediators of immediate hypersensitivity?
arachidonic acid derived products
What enzyme converts membrane phospholipids to arachidonic acid?
Phospholipase A2
Leukotrienes and protaglandins are produced by what enzymes, respectively from AA?
5-lipoxygenase and cyclooxygenase
What are the most potent vasoactive and spasmogenic agents known?
Leukotrienes C4 and D4
What leukotriene is highly chemotactic for neutrophils, eosinophils, and monocytes
B4
What is the most abundant mediator produced in mast cells by the COX pathway?
PGD2
What does PDG2 do?
intense bronchospasm and increased mucus secretion
What is a lipid mediator produced by some mast cells but not derived from AA?
PAF
What does PAF do?
- platelet aggregation
- release of histamine
- bronchospasm
- increased vascular permeability
- vasodilation
What are often an abundant leukocyte population in the late phase reaction of a type I hypersensitivity?
eosinophils
What recruits eosinophils?
eotaxin
What is the most potent eosinophil-activating cytokine known?
Th2 cytokine IL-5
What are the 2 eosinophil proteins that damage tissue?
Major basic protein and eosinophil cationic protein
An increased propensity to develop immediate hypersensitivity reactions is called what?
atopy
Atopic individuals tend to have higher levels of what compared to the general population?
Serum IgE and IL-4 producing Th2 cells
Studies of patients with asthma reveal linkage to polymorphisms in several genes on what chromosome?
5 and also 6, close to HLA complex
When an immediate hypersensitivity reaction is triggered by non-antigenic stimuli such as temperature extremes and exercise, Th2 and IgE are not involved and these are called what?
nonatopic allergy
4 examples of disorders caused by immediate hypersensitivty (type 1)?
- Anaphylaxis
- Bronchial asthma
- Allergic rhinitis
- food allergies
What is anaphylaxis characterized by?
- vascular shock
- widespread edema
- difficulty breathing
The membrane attack complex formed from complement is effective in killing what?
cell that have thin cell walls such as Neisseria bacteria
Name the Disease: antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission and therefore cause muscle weakness
myasthenia gravis
Name the disease: antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism
Graves Disease
What are the common sites of immune complex deposition for type III hypersensitivity?
kidney, joints, and small blood vessels
What are the 3 phases of systemic immune complex disease?
- Formation of immune complexes
- Deposition of immune complexes
- inflammation and tissue injury
The cell-mediated type of hypersensitivity (type IV) is caused by what?
inflammation resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells
What is the prototype of T-cell mediated inflammation?
delayed-type hypersensitivity (DTH)
Th1 cells produce inflammation by what cells?
macrophages
Th17 cells produce inflammation by what cells?
neutrophils
What is the classic example of DTH?
tuberculin reaction
Tuberculin reaction is produced by the intracutaneous injection of what?
purified protein derivative (PPD)
Morphologically, DTH is characterized by what?
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing”
Sustained activation of a DTH reaction turns macrophages into what and forms a what?
epitheloid cells; granuloma
Granulomatous inflammation is typically associated with what?
strong Th1-cell activation and high level production of cytokines such as IFN-gamma
Autoreactive T cells react against CNS myelin
multiple sclerosis
diversity of antibodies directed against DNA, platelets, red cells, and protein-phospholipid complexes resulting in widespread lesions throughout the body
SLE
antibodies to basement membranes of lung and kidney inducing lesions in these organs
Goodpasture syndrome
What protein stimulates expression of some peripheral tissue-restricted self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens?
AIRE
mutations in AIRE gene are the cause of what?
autoimmune polyendocrinopathy
If a maturing CD4+ T cell sees a self antigen in the thymus and doesn’t die, it turns into what?
regulatory T cells
When lymphocytes that recognize self antigens and are rendered functionally unresponsive it is called what?
anergy
What are the 2 costimulatory molecules that are inhibitory and can cause anergy?
CTLA-4 and PD-1
What has higher affinity for B7 molecules, CD28 or CTLA-4?
CTLA-4
What are the best defined regulatory T cells?
CD4+ cells that express high levels of CD25, the alpha chain of the IL-2 receptor, and FOX3P
In humans, mutations of FOX3P cause what?
IPEX
The inhibitory activity of Treg cells may be mediated in part by the secretion of what?
IL-10 and TGF-beta
Treg cells express CTLA-4 and reduced ability of APCs to activate T cells via what?
CD28
T cells that recognize self antigens may express what pro-apoptotic member of the Bcl family?
BIM without antiapoptotic Bcl-2 and Bcl-x
Death receptor Fas
CD95
mutation of the FAS gene leads to what in humans?
autoimmune lymphoproliferative Syndrome (ALPS)
What are the immune privileged sites?
Testis, Eye, brain
polymorphisms in what gene are associated with rheumatoid arthritis, type I diabetes, and several other autoimmune diseases?
PTPN22 which encodes tyrosine phosphatatase
Polymorphisms in what gene are associated with Crohn Disease?
NOD2
polymorphisms in what genes are associated with multiple sclerosis?
IL-2 receptor (CD25) and IL-7 receptor
SLE predominantly affects what gender?
women during reproductive years
Antinuclear antibodies (ANAs) can be grouped into what 4 categories?
- antibodies to DNA
- antibodies to histones
- antibodies to nonhistone proteins bound to RNA
- antibodies to nucleolar antigens
What are the 4 patterns of staining for ANAs
- Diffuse
- speckled
- Anti-centromeric
- Nucleolar
Antibodies to what are virtually diagnostic of SLE?
double stranded DNA and the so-called Smith (Sm) antigen
Lupus patients may have a false positive test for what?
syphilis
What drugs can induce an SLE-like response in humans?
- hydralazine
- procainamde
- D-penicillamine
Any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell is called what?
LE cell
Typically the presentation of SLE is a young woman with some but not necessarily all of what of the following features?
- butterfly rash over the face
- fever
- pain but no deformity in one or more peripheral joints
- pleutitic chest pain
- photosensitivity
Chronic Discoid Lupus Erythrmatosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare. It is characterized by what?
-Presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy. Usually face and scalp
How do you distinguish Subacute Cutaneous Lupus Erythematosus from Chronic discoid lupus erythematosus?
- The skin rash tends to be widespread, superficial and non scarring
- Strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype
Name the Disease: chronic disease characterized by dry eyes and dry mouth resulting from immunologically mediated destruction of the lacrimal and salivary glands
Sjogren syndrome
Keratoconjuctivitis sicca
dry eyes
xerostomia
dry mouth
About 75% of Sjogren syndrome patients have what?
rheumatoid factor (an antibody reactive with self IgG)
What are the most important antibodies found in Sjogren syndrome patients?
ones directed against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La)
What cytoskeletal protein is possibly implicated in Sjogren syndrome?
alpha-fodrin
Most common people to get Sjogren?
women between 50 and 60
Keratoconjunctivitis causes what symtoms?
blurring of vision, burning, and itching and thick secretions accumulate in conjunctival sac
Xerostomia results in what symptoms?
- Difficulty swallowing solid foods
- decrease in ability to taste
- cracks and fissures in the mouth
- dryness of the buccal mucosa
Enlargement of what gland is seen in half the patients of Sjogren?
parotid
What is essential for the diagnosis of Sjogren syndrome?
Biopsy of the lip to examine minor salivary glands
Systemic Sclerosis (Scleroderma) is characterized by what 3 things?
- chronic inflammation thought to be the result of autoimmunity
- widespread damage to small blood vessels
- progressive interstitial and perivascular fibrosis in the skin and multiple organs
What are the 2 categories of systemic sclerosis?
- Diffuse scleroderma
- limited scleroderma
Diffuse scleroderma is characterized by what?
widespread skin involvement at onset, with rapid progression and early visceral involvement
Limited scleroderma is characterized by what?
involvement is often confined to fingers, forearms, and face. Visceral involvement occurs late
Some patients with Limited scleroderma develop a combination of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. This is called what?
CREST syndrome
The cause of systemic sclerosis is not known but the disease likely results from what three interrelated processes?
- autoimmune responses
- vascular damage
- collagen deposition
The CD4+ cells found on the skin of systemic sclerosis patients produce what cytokines that can stimulate transcription of genes that encode collagen and other ECM proteins (fibronectin) in fibroblasts.
TGF-beta and IL-13
What is the distinctive feature of systemic sclerosis?
striking cutaneous changes notably skin thickening
Raynaud phenomenon is what?
severe vasoconstiction of extremities
What is the most life threatening aspect of systemic sclerosis?
malignant hypertension with subsequent development of fatal renal failure
Mixture of the features of SLE, systemic sclerosis, and polymyositis?
Mixed connective Tissue Disease
What does mixed connective tissue disease typically present with?
- synovitis of fingers
- Raynaud phenomenon
- mild myositis
Grafts exchanged between individuals of the same species?
allografts
Grafts from one species to another?
Xenografts
What is the APC in the direct pathway of allorecognition?
DONOR dendritic cells
What is the mechanism of killing in the direct pathway of allorecognition?
CD4+ and CD8+
What is the APC for the indirect pathway of allorecognition?
HOST
What is the result of the indirect pathway of allorecognition?
delayed hypersensitivity
what is the mechansim of killing in the indirect pathway of allorecognition?
T-cell cytokine production and inflammation. CD8+ CTLs CANNOT kill graft cells
What is seen in acute cellular rejection? also called acute T cell-mediated rejection
- Clinical and biochemical signs of the organ failure
- Cytokines secreted by activated CD4+ T cells
- Increased vascular permeability and local accumulation of mononuclear cells
Most common glomerular disease associated with SLE?
Diffuse lupus nephritis (class IV) also most common
What organs are not affected in drug induced lupus Erythematosus?
Kidneys and CNS
Early Sjogren syndrome shows what pathology?
Mixture of polyclonal T and B cells
Over time what can emerge in Sjogren syndrome?
A dominant B-cell clone-> marginal Zone Lymphoma
Other clinical features of systemic sclerosis
- Dysphagia from esophageal fibrosis (hypomotility)
- Respiratory diffuculty
- Myocardial fibrosis-> arrhthmias/cardiac failure
- Renal: mild proteinuria/malignant hypertension
IgG4 related Disease often affects who?
middle-aged and older men
Enlargement and fibrosis of salivary and lacrimal glands
Mikulicz syndrome
IgG4 related Disease is characterized by what?
- Tissues are infiltrated by IgG4 antibody-producing plasma cells and lymphocytes (mainly T cells)
- Storiform Fibrosis
- Obliterative phlebitis
- usually increased serum IgG4
What happens in chronic rejection?
- Lymphocytes react against alloantigens in the vessel wall
- secrete cytokines that induce local inflammation
What occurs when PREFORMED antidonor antibodies are present in the circulation of the recipient?
hyperacute rejection
Hyperacute refection can develop in persons with what/
- previous transplant
- prior blood transfusions
- multiparous women
What is it called when Antidonor antibodies are produced after transplantation?
Acute antibody-mediated rejection
Acute antibody-mediated rejection initially targets what/
graft vasculature
Which allele matching shows substantial benefit in kidney transplants?
HLA-A, B, and DR
In immunosuppressive therapy, what does mycophenolate mofetil do?
inhibits lymphocyte proliferation
in immunosuppressive therapy, What does Tacrolimus (FK506) do?
inhibits T cell functions
What does IVIG do?
suppresses inflammation
What is plasmapheresis used for?
Used in cases of severe antibody-mediated rejection
What virus is common due to immunosuppressive therapy in kidney transplants?
Polyoma virus
What latent viruses can become reactivated when given immunosuppressive therapy?
- EBV-induced lymphomas
- HPV induced squamous cell carcinoma
- Kaposi sarcoma (HHV8)
What is hematopoietic stem cell transplantation used for?
- hematologic malignancies
- Bone marrow failure syndromes (aplastic anemia)
- Inherited stem cell defects (sickle cell, thalassemia, and immunodeficient states)
How are hematopoietic stem cells harvested?
give CSF and harvest from peripheral blood
-also can be obtained from umbilical cord blood of newborn infants
What occurs when transplant cells recognize alloantigens in the host and attack host tissues?
Graft-vs-Host Disease (GVHD)
When is GVHD most common?
bone marrow (HSC ) tansplantation
what is needed to minimize GVHD?
HLA matching
The majority of clinical manifestations of Acute GVHD come from what organs?
- immune system
- skin
- liver
- intestines
What is a way to eliminate GVHD?
knock out Donor T cells before transfusion
What are the consequences of knocking out Donor T cells?
- Recurrence of tumor in leukemia patients
- Increased incidence of graft failures
- increased rates of EBV-related B-cell lymphoma
Infants with SCID present with what?
- Prominent Thrush (oral candidiasis)
- Extensive diaper rash
- failure to thrive
Some infants with SCID can develop a GVHD type rash how?
maternal T cells are transferred across the placenta and attack the fetus
SCID patients are extremely susceptible to what infections?
- Candida albicans
- pneumocystic jiroveci
- pseudomonas,
- CMV
- Varicella
Death of SCID patients occurs within the first year of life unless they get what?
HSC (BMT) transplantation or maybe gene therapy
SCID is most commonly what type of inheritance?
X linked
Failure of B-cell precursors to develop into mature B cells is what?
X Linked (Bruton) Agammaglobulinemia
What infections are common for X-linked Agammaglobulinemia?
Respiratory tract- haemophilus influenzae, Streptococcus pneumoniae, staphylococcus aureus
Viruses in blood or mucus- enterovirus, poliovirus, coxsackievirus
Giardia Lamblia (intestinal protozoan)
When do you see symptoms of X-linked Agammaglobulinemia?
after 6 months once maternal IGs are depleted
about 35% of patients with X-linked Agammaglobulinemia will develop what autoimmune disease?
Arthritis and dermaomyositis
How do you treat X-linked Agammaglobulinemia?
IVIG
T-cell deficiency that develops from failure of development of 3rd an 4th pharyngeal pouches
DiGeorge Syndrome (Thymic hypoplasia)
What does DiGeorge Syndrome give rise to?
-Thymus-> loss of T cell mediated immunity, poor defense against certain fungal and viral infections
Parathyroids->Hypocalcemia –>tetany
- Some C cells of thyroid aren’t formed
- Ultimobranchial body–> congenital defects of the heart and great vessels
- Abnormal appearance of mouth, ears, and facies
DiGeorge syndrome is considered a component of what deletion?
22q11 deletion syndrome
Hyper-IgM syndrome is caused by what?
defect in ability of helper T cells to deliver activating signals to B cells and macrophages
Hyper-IgM syndrome is what inheritance?
X-linked (70%) or autosomal recessive
What type of infections are common with Hyper-IgM syndrome?
pyogenic infections
Hyper-IgM syndrome patients susceptible to Pneumocystis jiroveci pneumonia have what mutations?
CD40L
Occasionally IgM antibodies react with blood cells to cause what?
- autoimmune hemolytic anemia
- thrombocytopenia
- neutropenia
Common Variable Immunodeficiency (CVID) affects what antibody classes?
usually all but sometimes only IgG
How do you differentiate CVID from X-linked agammaglobulinemia?
normal B cells numbers but they just aren’t able to differentiate into plasma cells
Isolated IgA deficiency is seen in association with what infections?
- Toxoplasmosis
- Measles
- other viral infections
Symptomatic patients with isolated IgA deficiency will have what?
- Recurrents Sinopulmonary infectons
- Diarrhea
- High frequency of respiratory tract allergy and autoimmune diseases
What the issue with blood transfusion in isolated IgA deficiency?
if it’s IgA containing blood the IgA behaves like a foreign substance and they can develop severy/fatal anaphylactic reactions
Immunodeficiency can be Associated with systemic diseases such as what?
- Wiskott-Aldrich syndrome
- Ataxia Telangiectasia
Wiskott-Aldrich Syndrome inheritance?
X-linked
highlights of Wiskott-Aldrich?
Thrombocytopenia, eczema, recurrent infection –> early death
Treatment of Wiskott Aldrich?
HSC transplantation
inheritance of Ataxia Telangiectasia?
Autosomal recessive
highlights of Ataxia telangiectasia?
- abnormal gait
- vascular malformations
- neuro deficits
- increased incidence of tumors
- immunodeficiency
Where is HIV-1 most common?
- US
- Europe
- Central Africa
where is HIV-2 common?
West Africa and India
HIV virus core contains what protein?
Major Capsid protein p24
What is used to diagnose HIV infection?
ELIZA test
HIV core contains what viral enzymes?
- protease
- Reverse transcriptase
- Integrase
what is the HIV core surrounded by?
Matrix protein called p17
What studs the viral envelope of HIV and is critical for HIV infections of cells?
gp120 and gp41
HIV first infects what cells that have what marker?
- T cells, dendritic cells, and macrophages
- CD4
What on HIV cells binds to CD4?
gp120
After CD4 and gp120 bind, they both bind to what?
chemokine receptor
What is used for HIV membrane penetration?
gp41
What helps distinguish what strain of HIV?
which chemokine receptor is used
R5 strain uses what receptor?
CCR5
R5 strain preferentially infects cells of what lineage?
monocyte/macrophage (M-tropic)
What HIV strain uses CXCR4 receptor
X4
X4 strain preferentially infects what cells?
T cells (T-tropic)
What strain can infect both types of cells?
R5X4
Why does HIV have a hard time infecting naive T cells?
they contain an enzyme that mutates the HIV genome
Stimulated cells with an HIV infection leads to what?
release of NF-kappaB to nucleus –>increased HIV DNA transcription
HIV-1 uses what gene to infect and multiply in terminally differentiated non-dividing macrophages?
vpr gene
Dendritic cells pick up HIV and present it to CD4+ T cells via what?
Lectin-like receptor
Clinical presentation of the initial spread of HIV and host response
Acute retroviral syndrome
Acute Retroviral syndrome typically occurs when?
3-6 weeks after infection
When does Actue retroviral syndrome resolve?
after 2-4 weeks
Symptoms of acute retroviral syndrome?
- sore throat
- Myalgias
- fever
- weight loss
- fatigue
- rash
- cervical adenopathy
- diarrhea
- vomiting
what is used to predict the rate of progression of HIV?
viral load
During the clinical Latency period of HIV, what are the possible clinical symptoms?
- Oral candidiasis (thrush)
- vaginal candidiasis
- herpes Zoster
- maybe tuberculosis
- autoimmune thrombocytopenia
What does HIV down modulate on infected cells?
Class I MHC
Combination of 3-4 drugs that block different steps of HIV life cycle
HAART
What are the adverse side effects of HAART?
- lipoatrophy (loss of facial fat)
- Lipoaccumulation (excess fat deposition centrally)
- elevated lipids
- insulin resistance
- peripheral neuropathy
- premature cardiovascular kidney and liver disease
What can develop from HAART?
immune reconstitution inflammatory syndrome
AL from Ig light chains is major fibril protein in what?
multiple myeloma
AA from SAA is major fibril protein in what?
chronic inflammatory diseases
Abeta2m from class I MHC beta2 microglobulin is major fibril protein in what?
chronic renal disease
