USMLE - Immune System Part 2

Self-reactive T cells become non reactive without costimulatory molecule
B cells also become anergic but tolerance is less complete than in T cells

S Pyogenes and S aureus

| Cross link β region of T cell receptor to MHCII on APC activating T cell and producing massive release of cytokines

Lipopolysaccharide
Gram neg
Directly stimulate Macrophages by binding to CD14
Th not involved

Salmonella (2 flagellar variants), Borrelia (relapsing fever), Neisseria gonorrhoeae (pilus protein)

Influenza
Major = Shift
Minor = Drift

Trypanosomes (programmed rearrangement)

Receiving preformed Abs
Rapid
Short (Ab half life is 3 weeks)
IgA in breast milk, Antitoxin, Humanized monoclonal Abs

"To Be Healed Rapidly"

| Tetanus toxin, Botulinum toxin, HBV, Rabies virus

Exposure to foreign Ag
Slow
Long lasting
Natural infection, vaccines, toxoid

HBV or Rabies

Cellular response

| Measles, Mumps, Rubella, Varicella, Yellow Fever, Polio (Sabin)

Humoral Immunity

| Cholera, HAV, Rabies, Polio (Salk)

I, II, and III

Anaphylactic and Atopic
Free Ag cross-links IgE on presensitized mast cells and basophils triggering release of vasoactive amines that act at post-capillary venules (histamine)
Rapid because of preformed Ab
Skin test for specific IgE

Cytotoxic. Ab mediated
IgM, IgG bind to fixed Ag on "enemy" cell leading to cellular destruction
Opsonization, Complement activation, Ab-Dependent Cell-Mediated cytotoxicity (ADCC) due to NK cells
Direct and Indirect Coombs' Test

Immune Complex

| Ag-Ab (IgG) complex activates complement which attracts Neutrophils which release lysosomal enzymes

Immune Complex Disease
ICs are deposited in membranes where they fix complement leading to tissue damage
5-10 days after exposure
More common than Arthus
Drugs acting as haptens
Fever, Urticaria, Arthralgias, Proteinuria, Lymphadenopathy

Local Subacute Ab mediated hypersensitivity type III reaction
Intradermal injection of Ag induces Abs which form Ag-Ab complexes in the skin which activate complement
Edema, Necrosis
Immunofluorescent staining
Less common than serum sickness

Delayed T cell mediated reaction

Sensitized T lymphocytes encounter Ag and release lymphokines leading to macrophage activation. No Ab involvement

Not transferable in serum

"4Ts: Tcells, Transplant rejection, TB skin test, Touching (contact dermatitis)"

Patch test, PPD

"ACID"

I: Anaphylactic and Atopic

II: Cytotoxic

III: Immune Complex

IV: Delayed (cell mediated)

Anaphylaxis (allergy)

| Allergic and Atopic disorders (Rhinitis, Hay Fever, Eczema, Hives, Asthma)

"Go PIE TRAP"

Goodpasture's Syndrome

Pernicious Anemia

Idiopathic Thrombocytopenic Purpura

Erythroblastosis Fetalis

Acute Hemolytic Transfusion Reaction

Rheumatic Fever

Autoimmune Hemolytic Anemia

Bullous Pemphigoid, Pemphigus Vulgaris

"LAPPS"

SLE

Arthus

Polyarteritis nodosa

PSGN

Serum Sickness

"Ms PuGG's CD"

MS

PPD test for TB

Gullian Barre

Graft vs Host

Contact Dermatitis (Poison Ivy, Nickel allergy)

Type I
Urticaria, Pruritus, Wheezing, Fever
Antihistamines

Severe
IgA deficient individuals must receive blood that lacks IgA
Dyspnea, Bronchoconstriction, Hypotension, Respiratory Arrest, Shock

II
Host Ab against donor HLA Ags and leukocytes
Fever, Headaches, Chills, Flushing

II

Intravascular hemolysis (ABO blood group incompatibility) or Extravascular hemolysis (host Ab reaction against foreign Ag or donor RBC)

Fever, Hypotension, Tachycardia, Flank Pain, Hemoglobinemia (intravascular), Jaundice (extravascular)

SLE, nonspecific

SLE

Drug induced SLE

RA

CREST

Scleroderma (diffuse)

Primary Biliary Cirrhosis
Celiac Disease
Goodpasture's Syndrome
Pemphigus vulgaris

Hashimoto's Thyroiditis
Polymyositis, Dermatomyositis
Sjogren's
Mixed connective tissue disease

Autoimmune hepatitis
DM1
Wegeners
Microscopic polyangiitis, Churg Strauss syndrome

Sepsis
CMV, EBV, VZV, Chronic Respiratory and GI viruses
Candida, PCP

Encapsulated bacteria "SHiN SKiS"
Enteroviral Encephalitis, Poliovirus
GI Giardiasis (no IgA)

Staph, Burkholderia cepacia, Serratia, Nocardia
N/A
Candida, Aspergillus

Neisseria
N/A
N/A

Defect in BTK (a tyrosine kinase gene) --> no B cell maturation
Recurrent bacterial infections (bacteria, enterovirus, Giardia- get these 3 whenever defect in immunoglobulins) after 6 months of age
Norma pro-B cells, ↓ # of B cells, ↓ Immunoglobulins of all classes

Most common primary immunodeficiency
Majority Asymptomatic. Sino-Pulmonary Infections, GI infections, Autoimmune disease, Anaphylaxis to IgA containing blood products
Low IgA with normal IgM and IgG. False positive βhCG test due to heterophile Ab

Defect in B cell maturation by many causes
Acquired in 20s-30s
Infections with bacteria, enterovirus, Giardia- get these 3 whenever defect in immunoglobulins
Autoimmune disease, Lymphoma, Sinopulmonary infections
Normal # of B cells with ↓ Plasma cells and Immunoglobulin

DiGeorge Syndrome
Failure to develop 3rd and 4th Pharyngeal Pouches
22q11 deletion
Tetany (hypocalcemia), Recurrent viral/fungal infections (T cell deficiency), Congenital Heart and Great Vessel Defect
↓ T cells, ↓ PTH, ↓ Ca
Absent Thymic Shadow on CXR

↓ Th1 response
Disseminated Mycobacterial Infections
↓ IFNγ

Job's Syndrome
Th1 cells fail to produce IFNγ leading to inability to attract neutrophils
"FATED"
course Facies, cold (non inflamed) staphylococcal, Abscesses, retained primary Teeth, ↑IgE, Dermatologic problems (eczema)
↑IgE

T cell dysfunction --> Candida albicans infection of skin and mucous membrane

Combined B and T cell disorder

Defective IL2 receptor (most common, X linked) or Adenosine Deaminase deficiency

Failure to thrive, Chronic Diarrhea, Thrush. Recurrent viral, bacterial, fungal, and protozoal infections

No Thymic shadow

No Germinal centers on lymph node biopsy, ↓ T cell recombinant Excision Circles (TREC)

No B or T cells in peripheral blood

Bone Marrow Transplant

Defect in ATM gene coding for DNA repair enzyme
Cerebellar defects (ataxia), Spider angiomas (Telangiectasia), IgA deficiency
↑AFP

Defective CD40L on Th cells = inability to class switch
Severe pyogenic infections in early life
↑IgM, ↓ IgG, IgA, and IgE

XL
WASP gene mutation = T cells unable to reorganize actin cytoskeleton
"TIE"
Thrombocytopenic Purpura, Infections, Eczema
↑IgE, ↑IgA, ↓IgM, Thrombocytopenia

Phagocyte Dysfunction
Defect in LFA1 integrin (CD18) protein on phagocytes
Recurrent bacterial infections, absent pus formation, Delayed separation of umbilical cord
Neutrophilia

Phagocyte dysfunction
AR
Defect in lysosomal trafficking regulator gene --> MT dysfunction in phagosome-lysosome fusion
Recurrent pyogenic infections by Staph and Strep, Partial Albinism, Peripheral Neuropathy
Giant Granules in Neutrophils

Phagocyte dysfunction
Lack of NADPH oxidase --> ↓ ROS and absent respiratory burst in neutrophils
Susceptibility to catalase + organisms (S aureus, E coli, Aspergillus)
Abnormal dihydrorhodamine (DHR) flow cytometry test
Nitroblue Tetrazolium due reduction test no longer preferred

Synteneic Graft

Minutes
Type II: Preformed antidonor Ab
Occludes graft vessels causing ischemia and necrosis

Weeks
Cell mediated reaction: CTLs react against foreign MHC
Reversible with immunosuppression
Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate

Months to years
Non-self MHCI recognized as self and presents non-self Ag
Irreversible
T cell and Ab mediated vascular damage (obliterative vascular fibrosis), Fibrosis of graft tissue and blood vessels

Varies
Grafted T cells attack host
Maculopapular rash, Jaundice, HSM, Diarrhea
Usually in Bone Marrow and Liver Transplants
Potentialy beneficial in Bone Marrow Transplant

Binds Cyclophilins. Complex blocks differentiation and activatino of T cells by inhibiting Calcineurin thereby preventing production of IL2 and its receptor
Suppress organ rejection. Autoimmune disorders
Nephrotoxicity, HTN, Hyperlipidemia, Hyperglycemia, Tremor, Gingival Hyperplasia, Hirsutism

FK506
Binds FK binding protein thereby inhibiting calcineurin and secretion of IL2 and other cytokines
Organ transplant
Nephrotoxicity, HTN, Hyperlipidemia, Hyperglycemia, Tremor

Rapamycin
Inhibits mTOR thereby inhibiting T cell proliferation in response to IL2
Kidney transplant w/ cyclosporine and corticosteroids. Drug Eluting Stents
Hyperlipidemia, Thrombocytopenia, Leukopenia

Antimetabolite precursor to 6MP that interferes with the metabolism and synthesis of nucleic acids. Toxic to proliferating lymphocytes
Kidney transplantation, Autoimmune disorders (including glomerulonephritis and hemolytic anemia)
Bone Marrow Suppression

OKT3
Ab that binds CD3 on T cell surface. Blocks cellular interaction with CD3 protein responsible for T cell signal transduction
Kidney Transplant
Cytokine release syndrome, Hypersensitivity Reaction

Aldesleukin

| Renal Cell Carcinoma, Metastatic Melanoma

Epoetic Alfa

| Anemias (especially renal failure)

Filgrastim

| Recovery of bone marrow

Sargramostim

| Recovery of Bone Marrow

HBV, HCV, Kaposi Sarcoma, Leukemias, Malignant Melanoma

MS

Chronic Granulomatous Disease

Oprelvekin

| Thrombocytopenia

Thrombocytopenia

anti IgE Ab used in asthma

Anti CD20 Ab used in B cell Non-Hodgkin's Lymphoma

Anti GP IIb/IIIa Ab used to prevent cardiac ischemia in unstable angina and in pts treated with percutaneous coronary intervention

Anti GP IIb/IIIa Ab used to prevent cardiac ischemia in unstable angina and in pts treated with percutaneous coronary intervention