Day 2.3 Immuno Flashcards
What HPS types are Ab-mediated?
Type I
Type II
Type III
(Type IV is Tcell mediated)
How are Type II and Type III different in terms of Ab?
Type II has Ab against self. This induces macrophages to eat the self and causes tsu dmg.
Type III has Ab against non-self, and it’s the Ab-Ag complex that gets deposited into tissues. This induces macrophages to eat the complexes and cause dmg.
In both cases, the dmg is due to macrophages.
Note: Some disorders which feature Type III and Type IV HPS have anti-self Ab. Just bc there is anti-self Ab doesn’t mean the rxn will be Type II.
But, all Type II rxns are mediated by anti-self Ab.
How long does it take for…
Type I HPS?
Type III?
Type IV?
Type I = 15 min
Type III = 5-12 hrs
Type IV = 24-48 hrs (delayed)
Type I HPS
Anaphylactic and atopic.
Free Ag cross-links IgE on presensitized mast cells and basophils- these degranulate and rls vasoactive amines that act at post-capillary venules (histamine).
Causes edema.
Rapid
How do you test for Type I HPS?
Scratch test (scratch back and put Ag there, wait for 15 min to see well-defined wheal and flare.
What is wheal and flare?
Wheal = hive Flare = red
Examples of Type I HPS
Anaphylaxis: bee sting, food/drug allergy
Allergic/Atopic: rhinitis, hay fever, eczema*, hives, asthma
Even tho eczema is Tcell mediated, it is a Type I bc it’s fast!
Type II HPS
Antibody mediated- IgM, IgG bind to fixed Ag on “enemy cell” (which is actually self!), leading to lysis by complement, or to phagocytosis.
Cy-2-toxic.
Ab and complement lead to MAC.
Dz is usually specific to the tsu/site where Ag is found
What are the 3 mechanisms of a Type II HPS rxn?
- Ab opsonize cells or activate complement
- Ab recruit neutrophils and macrophages that incite tsu dmg
- Ab bind to normal cellular receptors and interfere w functioning.
What is the test for Type II HPS?
Coombs (direct and indirect)
Use a known marker that binds to Ab to see if the Ab are there.
What is a direct Coombs test?
Anti-Ig antibody is added to the patient’s RBC agglutinate to see if RBCs are coated with Ig.
What is an indirect Coombs test?
Normal RBCs are added to the patient’s serum agglutinate to see if the serum has anti-RBC surface Ig
Ex of Type II HPS rxn
Auto-immune hemolytic anemia
Pernicious anemia
ITP (Ab against plts)
Erythroblastosis fetalis (Rh incompatibility)
Acute hemolytic txfsn rxns (wrong blood type)
Rheumatic Fever
Goodpasture’s synd (vasculitis)
Bullbous pemphigold
Pemphigus vulgaris
Graves’ dz (Ab against TSH receptor- stim the receptor –> hyperthyroidism)
Myasthenia Gravis (Ab against Ach receptor)
Type II HPS: What is pernicious anemia?
Have Ab against intrinsic factor (IF) so Vit B12 can't be absorbed in the ilieum. B12 deficiency (neurologic problems)
Type II HPS: What is erythroblastosis fetalis?
Maternal Ab to a fetal RBC Ag. (Fetus is Rh+ but mom is Rh-, so mom makes Ab against fetus since it’s “foreign”).
Neonate has:
anemia d/t hemolysis of fetal RBC by maternal Ab
jaundice (Hb was broken down, so excess bilirubin –> jaund)
Hydrop fetalis (generalized fetal edema- fluid in lungs, peritoneum, tsus)
IU death.
Rh- moms don’t have Rh-D on the surface of the blood cells. When should they get anti-Rh-D Ig?
28 weeks (bc fetus can be born after this time)
Any traumatic event in which mom might be exposed to fetal RBC (ex: MVA)
W/in 3 days of delivery
Abortion or miscarriage
For which pregnancies will the mom’s anti-Rh Ab have an effect?
All pregnancies after the 1st one. (Incl if the first one ended in abortion/miscarriage).
The Ab develop in the 1st pregnancy, but are not in lg enough quantity to cause harm until 2nd pregnancy.
Type II HPS:
What is bullous pemphigoid and pemphigus vulgaris?
Bullous pemphigoid = Ab against hemidesmosomes
Pemphigus vulagaris = Ab against desmosomes / desmoglien
Both of these are Ab against epithelium, so they manifest in skin.
Type III HPS
Ab against non-self Ag, form Ag-Ab immune complexes and get deposited into tsu.
Ag-Ab (IgG) complexes activate complement, which attracts neutrophils.
Neutrophils rls lysosomal enz.
Imagine immune complex as 3 things stuck together: Ag-Ab-complement
5-12 hrs
What are 2 special kinds of Type III HPS?
Serum sickness
Arthus reaction
What is the mechanism of serum sickness?
Type III immune complex dz in which Ab to foreign proteins are produced (takes 5 days). Immune complexes form and are deposited in membranes, where they fix complement and cause dmg to the tsu.
In past before Abx, gave lots of Ab to the dz, so it would mk complexes and deposit in vessel walls (so, “serum” sickness). Now, it’s usually caused by drugs.
Symptoms of serum sickness?
Type III immune complex dz.
Fever, urticaria, arthralgias, proteinuria (and glomerulonephritis), and lymphadenopathy.
Occurs 5-10 days after Ag exposure, bc Ab to the Ag have to be produced.
What is the mechanism of Arthus reaction?
Type III HPS, local, sub-acute, Ab-mediated.
Intradermal injection of Ag (eg tetanus vaccine) induces Ab, which form Ag-Ab complexes in skin.
Test for it w. immunofluroescent staining.
Symptoms of Arthus rxn?
Type III HPS
Edema, necrosis, activation of complement.
5-12 hrs after intradermal injection of Ag.
Ex of Type III HPS
SLE Rheumatoid arthritis Polyarteritis nodosa Post-strep glomerularnephritis Serum sickness Arthus rxn HPS pneumonia (farmer's lung) Can be assoc'd with vasculitis and systemic manefestations
Type IV HPS
Delayed, T-cell mediated.
Sensitized Tcells encounter Ag and then rls lymphokines which lead to macrophage activation.
No Ab are involved.
24-48 hrs.
Bc it’s cell mediated, it is not transferable by serum.
Test: patch test (e.g. PPD for TB)
What are the 4 T’s of Type IV HPS?
T-lymphocytes (Tcell mediated)
Transplant rejections
TB skin tests
Touching (contact dermatitis)
Mnemonic for HPS rxns: ACID
ACID: Anaphylactic and Atopic = Type I Cytotoxic (Ab-mediated) = Type II Immune complex = Type III Delayed (Tcell mediated) = Type IV
Ex of Type IV HPS
DM Type I MS Guillian-Barre Synd Hashimoto's Thyroiditis Graft v Host dz PPD (test for M. TB) Contact dermatitis
What are ex of contact dermatitis (Type IV delayed HPS)
Poison ivy, oak
Nickel allergy- watch, belt buckle, sandal buckle
Anti-nuclear Ab (ANA)
SLE but also many other things: Sjorgrens Scleorderma Polymyositis Dermatomyositis Rheumatoid arthritis Juvenile arthritis MCTD
Anti-dsDNA, Anti-Smith
Specific for SLE
dsDNA = even more specific for renal dz in SLE
Anti-histone
Drug-induced lupus
Anti-IgG (Rhematoid Factor)
Rhematoid Arthritis.
This is IgM Ab attacking IgG
Anti-centromere
CREST Scleroderma
Anti-Scl70 (Anti-DNA topoisomerase I)
Diffuse Scleroderma
Anti-mitochondrial
Primary biliary cirrhosis
Anti-gliadin, Anit-endomysial
Celiac dz (malabs syndrome where villi of gut are severely atrophied) Gliadin - component of wheat
Anti-basement mbr
Goodpasture’s synd (renal dz, lung dz)
Anti-desmoglien
Pemphigus vulgaris
Anti-microsomal, anti-thyroglobulin
Hashimoto’s thyroiditis
Anti-Jo-1
Polymyositis
Dermatomyositis
Anti-SSA (Anti-Ro)
Sjogren’s
SLE
Anti-SSB (Anti-La)
Sjogren’s
SLE
Anti-U1 RNP (ribonucleoprotein)
MCTD (mixed CT dz)
Anti-smooth muscle
Autoimmune hepatitis
Anti-glutamate decarboxylase (Anti-glutamic acid decarboxylase)
DM Type I
c-ANCA (Anti-neutrophil cytoplasmic An)
Wegener’s granulmatosis
p-ANCA
Vasculitis:
microscopic polyangitis
Chrug-Strauss
mpo-ANCA (myeloperoxidase)
Pauci-immune crescentic glomerulonephritis
Anti-TSH receptor
Graves’ Dz (HYPERthyroidism- the receptor is stimulated)
Anti-ACh receptor
Myasthenia Gravis
Illnesses with elevated ESR
Polymyalgia rhenmatica Temporal arthritis Disease activity in RA and SLE Infection, Inflammation, Malignancy Osteoarthritis- infection of bone, can be subclinical. if high ESR, increased suspicion; if not, can rule it out.
22q11 deletion syndromes
Due to aberrant devt of 3rd and 4th brachial pouches
CATCH-22:
Cleft palate
Abnormal facies
Thymic aplasia (–> Tcell deficiency)
Hypocalcemia (secondary to parathyroid aplasia)
DiGeorge = thymic, parathyroid, cardiac defects
Velocardiofacial syndrome = palate, facial, cardiac defects
Which immune deficiencies are B-cell disorders?
Bruton’s agammaglobulinemia
Hyper-IgM Syndrome
Selective Ig deficiency
CVID- common variable immunodeficiency
Which immune deficiencies are T-cell disorders?
Thymic aplasia (DiGeorge)
IL-12 receptor deficiency
Hyper IgE Syndrome (Job)
Chronic mucocutaneous candidiasis
Which immune disorders are combined B-cell and T-cell disorders?
SCID - severe combined immunodeficiency
Ataxia-telangiectasia
Wiskott-Aldrich syndrome
Which immune disorders are due to phagocyte dysfunction?
Leukocyte adhesion deficiency (Type I)
Chediak-Higashi syndrome (MT fn)
Chronic granulomatous dz (NADPH oxidase deficiency)
Which immunodeficiencies are X-linked?
WBC:
Wiskott-Aldrich
Bruton’s Agammaglobulinemia
Chronic Granuolmatous Dz (sometimes X-linked, not always)
Also one of the 3 types of Hyper-IgM Syndrome is X-linked (the type with no CD ligand)
What are the 3 types of Hyper-IgM syndrome?
Hyper-IgM = lots of IgM but low amts of other Ig’s.
- X-linked (no CD ligand)
- Autosomal Recessive (no CD40)
- NEMO deficiency
What is the defect in Bruton’s agammaglobulinemia?
X-linked recessive, so moreso in Boys (one of the WBC X-linked)
Defect in BTK, a tyrosine kinase gene –> blocks Bcell differentiation and maturation –> low levels of all Ig’s.
Px of Bruton’s agammaglobulinemia
Recurrent bacterial infections after 6 months (decreased maternal IgG) due to opsonization defect.
Low levels of all Ig’s so get lots of infections.
Labs for Bruton’s agammaglobulinemia
Normal pro-B
Decreased maturation, # of B cells
Decreased Ig of all classes
Defect in Hyper-IgM syndrome
Defective CD40L on Thelper cells –> inability of B cells to class switch because need CD40-CD40L binding to signal it. So, all Ig’s are stuck as IgM
Px of Hyper IgM syndrome
Severe pyogenic infections early in life.
Labs for Hyper IgM
Lots of IgM
very low IgG, IgA, IgE
No CD40L on flow cytometry for Tcells
Defect in Selective Ig Deficiency
Defect in isotype switching –> deficiency in a specific class of immunoglobulins. (Can be any, but IgA deficiency most common)
Px of Selective Ig Deficiency
Most pts are healthy, may not know.
Sinus/lung infections
Milk allergies and diarrhea
Assocd w atopy (allergy predisposition), asthma
Imp: Anaphylaxis on exposure to blood products with IgA.
Occurs in 1/600 pts of European descent
Labs for Selective Ig Deficiency
IgA deficiency is most common.
Failure to mature into plasma cells.
Decreased secretory IgA.
Defect in CVID (common variable immunodeficiency)
Defect in B cell maturation.
D/t many causes
Px of CVID
Can by acquired in 20s-30s
Increased risk of autoimmune dz, lymphoma, sinopulmonary infections.
Labs for CVID
Normal number of B cells but decreased plasma cells and Ig
Defect in DiGeorge Syndrome (thymic aplasia)
22q11 deletion
failure to develop 3rd and 4th brachial pouches
Px DiGeorge
No Thymus - no mature Tcells = recurrent viral, protozoal, fungal infections
No Parathyroid - no PTH - low Ca2+ = tetany
Congenital heart and great vessel defects
Facial abn - cleft palate, low ears, smooth phitrum, micrognathia (chin)
Labs DiGeorge
No thymus, parathyroid, so decreased T cells, decreased PTH, decreased Ca2+
No thymic shadow on CXR
What are the 2 signs for low Ca2+?
Chovstek’s sign- tap cheek- when facial nerve is tapped, facial muscles will contract (tetany)
Trosseau’s sign- Carpal spasm when tighten BP cuff (tetany)
Defect, Px, Labs in IL-12 receptor deficiency
Defect: Decreased Th1 response
Px: Disseminated mycobacterial infections
Labs: Decreased IFN-gamma (bc Th1 are not secreting it)
Defect in Job’s Syndrome (Hyper IgE)
Th cells fail to produce IFN-gamma So PMNs (neutrophils) don't respond to chemotactic stimuli (C5a, LTB4, IL-8)
Px of Job’s syndrome (IgE)
Triad: Eczema Recurrent cold abscesses (S. aureus) Course facial features: broad nose, frontal bossing of forehead, deep eyes, doughy skin. Also can have retained primary teeth- 2 rows of teeth! Job was FATED: Facies Abcesses (cold- noninflamed) Teeth retained E (hyper-IgE) Dermatologic (eczema)
What is the defect, Px, and Rx for chronic mucocutaneous Candidiasis?
Defect: Tcell dysfn
Px:
C. albicans infections of skin and mucous mbr
Rx: Ketoconazole (anti-fungal)
What is the defect in SCID?
Defect is in early stem cell differentiation (No Bcells, Tcells)
Can be caused by >7 diff gene defects.
Most common:
Adenosine deaminase deficiency (purine salvage pathway)
Defective IL-2 receptor (X-linked defect)
Failure to synth MHC-II Ag
Only defense is NK cells.
Px of SCID
Triad: 1. Recurrent infections- viral, bacterial, fungal, protozoal due to both B and T cell deficiency (chonic mucocutaneous candida, RSV, VZV, HSV, measles, flu, parainfluenza, PCP pneumonia) 2. Chronic diarrhea 3. FTT Plus no thymus on CXR (like DiGeorge)
Rx for SCID
Bone marrow txplt (no allograft rejection)
Labs for SCID
Decreased IL-2R (decreased Tcell activation) Increased adenine (toxic to B and T cells)- decreased dNTPs, decreased DNA synth.
What is ADA deficiency (Adenosine deaminase)
ADA converts Adenosine to Inosine in the purine salvage pathway.
Defective ADA means accumulation of deoxyadenosine, which leads to excess ATP and dATP. This causes imbalance in nucleotide pool, d/t fdbk inhibition of ribonucleotide reductase. This prevents DNA synth and therefore decreases lymphocyte count.
Mjr cause of SCID.
What is the defect in Ataxia-Telangiectasia?
Defect in DNA repair enz and IgA deficiency.
Px of Ataxia-Telangiectasia
Triad:
1. Cerebellar defects (ataxia) plus poor smooth pursuit of moving target w eyes
2. Spider angiomas (telangiectasia) when >5yo
3. IgA deficiency
Also have increased CA risk (lymphoma, acute leukemia) and radiatiion sensitivity (avoid xray)
Die at 25yo
If you see a 1 yo with poor smooth pursuit, how should you check for Ataxia-Telangiectasia?
Increased alpha-fetoprotein (in kids >8mo)
Defect in Wiskott-Aldrich syndrome
X-linked recessive (it’s an x-linked Wbc)
Progressive deletion of Bcells and Tcells
Px of Wiscott-Aldrich
WAITER: Wiscott Aldrich Immunodeficiency/Infection Thrombocytopenic purpura Eczema (unusual bc it's trunkal eczema) Recurrent pyrogenic infections- no IgM against capsular bacteria
Labs for Wiscott-Aldrich
Low IgM
High IgA, IgE
Defect in Leukocyte Adhesion Deficiency (Type 1)
Defect in LFA-integrin protein (CD18) on phagocytes. This means phagocytes can’t exit circulation. (Can’t “integrate” into tsu’s)
Px of Leukocyte adhesion deficiency (Type I)
Recurrent bacterial infections, absent pus formation
Delayed separation of umbilicus
Labs for Leukocyte adhesion deficiency (type 1)
Neutrophilia (high amt of neutrophils in blood)
Defect in Chediak-Higashi syndrome
Autosomal recessive
Defect in microtubular function with decreased phagocytosis
Defective LYST gene (lysosomal txprt)- can’t get the enz which degrade things into the lysosomes.
Defective phagocyte lysosome- see giant cytoplasmic granules in PMNs (can engulf, but can’t degrade once engulfed)
What is a PMN?
Polymorphonuclear Leukocytes (PMN, PML) aka granulocytes. There are three types of granulocytes: Neutrophils Eosinophils Basophils All have granules and lobed nuclei.
Px of Chediak-Higashi
Triad:
Partial albinism
Recurrent respi and skin infections (esp pyogenic infections by Staph and Strep)
Neurologic disorders- peripheral neuropathy
Defect in Chronic Granulomatous Dz
NADPH oxidase deficiency. Therefore phagocytes can’t generate ROS (e.g. superoxide and free radicals). Absent respiratory burst in neutrophils.
Px of Chronic Granulomatous Dz
Increase susceptibility to catalase+ organisms: Staph (esp S. aureus) E. coli Klebsiella Aspergillis Candida
Dx of Chronic Granulomatous Dz
Nitroblue tetrazolium dye test is negative.
Normal phagocytes engulf NBT dye and oxidize it, turning it from yellow to blue-black.
Pts w CGD can’t oxidize- so don’t see blue-black color.
Rx for Chronic Granulomatous Dz
Prophylactic TMP-SMX (bactrin)
INF-gamma can also help.
Where is the thymus derived from embryologically?
The 3rd and 4th brachial pouches, which are ENDODERM.
What are the type of grafts (allo, auto, etc)
Autograft- from self
Syngeneic graft - from identical twin or clone
Allograft - from nonidentical pt of same species
Xenograft- from different species
What are the 4 types of txplt rejection?
Hyperacute
Acute
Chronic
Graft-vs-Host dz
What is Hyperacute rejection?
Ab-mediated (Type II HPS)
Due to presence of pre-formed anti-donor Ab in the txplt recipient.
W/in minutes after txplt
What is Acute rejection?
Tcell-mediated d/t Cytotoxic Tcells reacting against foreign MHCs.
Weeks after txplt.
Reversible with immunosuppressants
What immunosuppressants can reverse Acute Rejection?
Cyclosporine
OKT3
What is Chronic rejection?
Tcell and Ab-mediated vascular dmg (obliterative vascular fibrosis)
Months-years after txplnt, Irreversible
The non-self MHC-I is seen by Cytotoxic Tcells as self MHC-I which is presenting foreign Ag, so it attacks.
Take immunosuppresants after txplt to delay this.
What is Graft-vs-Host dz?
Grafted immunocompetent Tcells proliferate in the immunocompromised host and reject foreign (to them) cells- which are the host’s cells.
Causes severe organ dysfn.
Mjr sympt: maculopapular rash, jaundice hepatosplenomegaly, diarrhea.
What does the Long Thoracic N innervate
Serratus Anterior
scapular winging if lesioned
What does the Suprascapular N. innervate?
Infraspinatus M (lateral rotator) Supraspinatus M (1st 10degrees of arm abduction)
What does the Lateral Pectoral Nerve innervate?
Pectoralis Mjr M.
What does the Upper Subscapular N. innervate?
Subscapularis M. (medial rotator)
What does the Thoracodorsal nerve innervate?
Latissimus Dorsi M.
What does the Lower Subscapular N. innervated?
Teres Mjr M. (medial rotator, extender, ADductor)
What does the Musculocutaneous N. innervate?
Flexor muscles:
Biceps brachii
Coracobrachialis
Brachialis
What does the Axillary N. innervate?
Deltoid m
What does the Radial N. innervate?
Extensors of forearm
Triceps
What does the Median nerve innervate?
Pronators.
Causes Pope’s blessing, Ape hand
What does the Ulnar N innervate
Interosseous, Lumbricals
Causes claw hand
What is Cori’s disease?
Deficiency in glycogen debranching enz.
Glycogen is stored in the liver. With debranching enz deficiency, it can’t undergo glycogenolysis (glycogen breakdown) to turn it into glucose.
With no glucose except from diet, there is hypoglycemia.
This leads to FTT.
What is Von Gierke’s Disease?
Glycogen storage disease- no glucose-6-phoshatase enz, so liver can’t make glucose from glycogen or from gluconeogenesis
