Immunology Pathophysiology

• Type I:
• -Anaphylaxis
• -Allergic and atopic disorders (e.g., rhinitis, hay fever, eczema, hives, asthma)
• Presentation: immediate, anaphylactic, atopic

• Type II:
• -Hemolytic anemia
• -Pernicious anemia
• -Idiopathic thrombocytopenic purpura
• -Erythroblastosis fetalis
• -Acute hemolytic transfusion reactions
• -Rheumatic fever
• -Goodpasture's syndrome
• -Bollous pemphigoid
• -Pemphigus vulgaris
• -Grave's disease
• -Myasthenia gravis

• Type III:
• -SLE
• -Rhematoid arthritis
• -Polyarteritis nodosum
• -Poststreptococcal glomerulonephritis
• -Serum sickness
• -Arthus reaction (e.g., swelling and inflammation following tetanus vaccine)
• -Hypersensitivity pneumonitis (e.g., farmer's lung)
• Can be associated with vasculitis and systemic manifestation

• Type IV:
• -Type 1 DM
• -Multiple sclerosis
• -Guillain-Barre syndrome
• -Hashimoto's thyroiditis
• -Graft-versus-host disease
• -PPD (test for M. tuberculosis)
• -Contact dermatitis (e.g., poison ivy, nickel allergy)
• Response is delayed and does not involve antibodies

• Allergic reaction: Type I hypersensitivity rxn against plasma proteins in transfused blood
• Presentation: Urticaria, pruritius, wheezing, fever
• Tx: antihistamines

• Anaphylactic reaction: Severe reaction. IgA-deficient individuals must receive blood products that lack IgA
• Presentation: Dyspnea, bronchospasm, hypotension, respiratory arrest, shock

• Febrile nonhemolytic transfusion reaction (FNHTR): Type II hypersensitivity reaction. 
• -Host Ab against donor HLA antigens and leukocytes
• Presentation: fever, ehadaches, chills, flushing

• Acute hemolytic transfusion reaction (HTR): Type II hypersensitivity reaction
• -Intravascular hemolysis (ABO blood group incompatibility)
• -extravascular hemolysis (host Ab reaction against foreign antigen on donor RBCs)
• Presentation: Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinemia (intravascular), jaundice (extravascular hemolysis)

• Antibody         -        Associated disorder
• Antinuclear antibodies (ANA)        SLE, nonspecific
• Anti-dsDNA, anti-Smith        SLE
• Antihistone        Drug-induced lupus
• Anti-IgG (rheumatoid factor)        Rhematoid arthritis
• Anticentromere        Scleroderma (CREST)
• Anti-Scl-70 (anti-DNA topoisomerase I)       Scleroderma (diffuse)
• Antimitochondrial        Primary biliary cirrhosis
• Antigliadin, antiendomysial        Celiac
• Anti-basement membrane        Goodpasture's syndrome
• Anti-desmoglein        Pemphigus vulgaris
• Antimicrosomal, antithyroglobulin        Hashimoto's thyroiditis
• Anti-Jo-1        Polymyositis, dermatomyositis
• Anti-SS-A (anti-Ro)        Sjogren's syndrome
• Anti-SS-B (anti-La)        Sjogren's syndrome
• Anti-Ul RNP (ribonucleoprotein)        Mixed connective tissue disease
• Anti-smooth muscle        Autoimmune hepatitis
• Anti-glutamate  decarboxylase        Type 1 diabetes mellitus
• c-ANCA        Wegener's granulomatosis
• p-ANCA        Other vasculitides

• No T cells:
• -Bacteria → sepsis
• -Virus → CMV, EBV, VZV, chronic infection with respiratory/GI viruses
• -Fungus/parasites → candida, PCP

• No B cells:
• -Bacteria → Encapsulated: Streptococcus, Staphylococcus, Haemophilus, Moraxella
• -Virus → Enteroviral encephalitis, poliovirus (live vaccine contraindicated)
• -Fungi/parasites →GI giardiasis (no IgA)

• No granulocytes:
• -Bacteri → Staphylococcus, Pseudomonas
• -Fungi/parasites → Candida, Nocardia, Aspergillus

• No complement:
• -Bacteria → Neisseria (no Mycobacterium avium complex)

• *B cell deficiencies→recurrent bacterial infections
• *T cell deficiencies → fungal and viral infections

• Bruton's agammaglobulinemia
• Hyper-IgM syndrome
• Selective Ig deficiency
• Common variable immunodeficiency (CVID)

X-linked recessive (↑ in Boys). Defect in BTK, a tyrosine kinase gene → blocks pro-B cells from forming pre-B cells

• Presentation: Recurrent bacterial infection after 6 months
• (↓ maternal IgG) due to opsonization defect.
• -Absence of thymic shadow

Labs: normal pro-B, ↓ maturation, ↓ number of B cells, ↓ immunoglobulins of all classes

Defective CD40L on helper T cells = inability to class switch

Presentation: severe pyogenic infections early in life

• Labs:
• ↑IgM, ↓↓ IgG, IgA, IgE

Defect in isotype switching → deficiency in specific class of immunoglobulins

• Presentation: sinus and lung infections, milk allergies and diarrhea,
• -Anaphylaxis on exposure to blood products with IgA

• Labs:
• IgA deficiency most common (failure to mature into plasma cells)
• -↓ secretory IgA

Defect in B cell maturation; many causes

Presentation: Can be acquired in 20s-30s; ↑ risk of autoimmune disease, lymphoma, sinopulmonary infections

• Labs:
• Normal number of B cells; ↓ plasma cells, immunoglobulin

• Thymic aplasia (DiGeorge syndrome)
• IL-12 receptor deficiency
• Hyper-IgE syndrome (Job's syndrome)
• Chronic mucocutaneous candidiasis

22q11 deletion; failure to develop 3rd and 4th pharyngeal pouches

• Presentation: 
• -Tetany (hypocalcemia)
• -recurrent viral/fungal infections (T-cell deficiency)
• -Congenital heart and great vessel defects

• Labs:
• THymus and parathyroids fail to develop →↓ T cells, ↓ PTH, ↓ Ca2+
• -Absent thymic shadow on CXR

↓ Th1 response

Presentation: Disseminated mycobacterial infection

Labs: ↓ IFN-γ

Th cells fail to produce IFN-γ→ inability of neutrophils to respond to chemotactic stimuli

• Presentation: FATED
• -coarse Facies
• -cold (noninglamed) staphylococcal Abscesses
• -retained primary Teeth
• -increased IgE
• -Dermatologic problems (eczema)

Labs: increased IgE

T-cell dysfunction

Presentation: Candida albicans infections of skin and mucous membrane

• Severe combined immunodeficiency (SCID)
• Ataxia-telangiectasia
• Wiskott-Aldrich syndrome

• Several types:
• -Defective IL-2 receptor (most common, X-linked)
• -adenosine deaminase deficiency
• -failure to synthesize MHC II antigens

• Presentation:
• -Recurrent viral, bacterial, fungal, protozoal infection due to both B- and T-cell deficiency
• -Absent thymic shadow
• -Absent germinal centers (lymph node biopsy)
• -Absent B cells (peripheral blood smear)

Tx:  bone marrow tranplant (no allograft rejection)

• Labs:
• - ↓ IL-2R = ↓ T-cell activation
• - ↑ adenine = toxic to B and T cells
• - (↓ dNTPs, ↓ DNA synthesis.)

Defects in the ATM gene, which codes for DNA repair enzymes

• Presentation: triad
• -Cerebellar defects (ataxia)
• -Spinder angiomas (telangiectasia)
• -IgA deficiency

Labs: IgA deficiency

X-linked recessive defect; progressive deletion of B and T cells

• Presentation: triad (TIE)
• -Thrombocytopenic purpura
• -Infections
• -Eczema

Labs: ↑ IgE, IgA; ↓IgM

• Leukocyte adhesion deficiency (type 1)
• Chediak-Higashi syndrome
• Chronic granulomatous disease

Defect in LFA-1 integrin (CD1) protein on phagocytes

• Presentation: 
• -Recurrent bacterial infections
• -absent pus formation
• -delayed separation of umbilicus

Labs: neutrophilia

• Autosomal recessive; defect in lysosomal regulating trfficking gene (LYST)
• -Microtubule dysfunction in phagosome-lysosome fusion

• Presentation:
• -Recurrent pyogenic infections by staph and strep
• -partial albinism
• -peripheral neuropathy

• Lack of NADPH
• -oxidase → ↓ reactive oxygen species (e.g. superoxide) and absent repiratory burst in neutrophils

• Presentation:
• -↑ susceptibility to catalase positive organisms (e.g. S. aureus, E. coli, Aspergillus)

Labs: Negative Nitroblue tetrazolium dye reduction test

• Autograft - from self
• Syngeneic graft - from identical twin or clone
• Allograft - from non-identical individual of same species
• Xenograft - from different species

• Hyperacute, within minutes
• Acute, weeks later
• Chronic, months to years
• Graft-versus-host, varies

Antibody mediated (type II) due to rpesence of preformed anti-donor antibodies in the recipient

Presentation: occludes graft vessels, causing ischemia and necrosis

• Cell-mediated due to CTLs reacting against foreign MHCs
• -Reversible with immunosuppressants (e.g., cyclosporine, OKT3)

Presentation: Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate

Class I-MHC_non-self is perceived by CTLs as class I-MHC_self presenting a non-self antigen

• Presentation: Irreversible
• -T-cell and antibody-mediated vascular damage (obliterative vascular fibrosis
• -fibrosis of graft tissue and blood vessels

• Graft immunocompetent T cells proliferate in the irradiated, immunocompromised disease host
• ...reject cells with "foreign" proteins, resulting in severe organ dysfunction

• Presentation:
• -Maculopapular rash
• -Jaundice
• -HSM
• -diarrhea
• -usually in bone marrow and liver transplant (lymphocyte rich organs)
• -Potentially beneficial in bone marrow transplant

• Cyclosporine
• Tacrolimus (FK506)
• Sirolimus (rapamycin)
• Daclizumab
• Azathioprine
• Muromonab-CD3 (OKT3)