Inmunology NBME

Chronic Granulomatous Disease

• Defect: NADPH oxidase deficiency

• Pathophysiology: Impaired respiratory burst → no superoxide → neutrophils can’t kill catalase-positive organisms

• Clinical: Recurrent infections with catalase(+) bacteria and fungi (e.g., S. aureus, Aspergillus)

• Diagnosis: Negative Nitroblue Tetrazolium (NBT) test or abnormal DHR flow cytometry

• Treatment: Prophylactic antibiotics, antifungals, interferon-γ

Leukocyte Adhesion Deficiency

• Defect: Absence of CD18 (integrin β2)

• Pathophysiology: Neutrophils can’t adhere to endothelium → impaired migration

• Clinical: Delayed umbilical cord separation, recurrent bacterial infections, no pus

• Diagnosis: Flow cytometry for CD18 expression

• Treatment: Bone marrow transplant

Chediak-Higashi Syndrome

• Defect: LYST gene (lysosomal trafficking regulator)

• Pathophysiology: Defective lysosome-phagosome fusion

• Clinical: Partial albinism, recurrent infections, neuropathy, giant granules in granulocytes

• Diagnosis: Peripheral smear shows giant granules

• Treatment: Bone marrow transplant

Myeloperoxidase Deficiency

• Defect: Myeloperoxidase enzyme

• Pathophysiology: No hypochlorite formation → reduced microbial killing

• Clinical: Recurrent Candida infections

• Diagnosis: Positive NBT, absent MPO staining

• Treatment: Supportive; often asymptomatic

DiGeorge Syndrome

• Defect: 22q11 deletion → failure of 3rd/4th pharyngeal pouch development

• Pathophysiology: Thymic aplasia → ↓T cells

• Clinical: Cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia (CATCH-22)

• Diagnosis: FISH, ↓T cells

• Treatment: Calcium supplementation, cardiac surgery, thymic transplant if needed

Wiskott-Aldrich Syndrome

• Defect: WAS gene mutation (X-linked)

• Pathophysiology: Impaired actin cytoskeleton in B/T cells

• Clinical: Thrombocytopenia, eczema, recurrent infections

• Diagnosis: ↓IgM, ↑IgA/IgE, small platelets

• Treatment: Bone marrow transplant

Severe Combined Immunodeficiency (SCID)

• Defect: IL-2Rγ (X-linked) or ADA deficiency

• Pathophysiology: Absence of functional T and B cells

• Clinical: Severe recurrent infections, chronic diarrhea, failure to thrive

• Diagnosis: ↓T/B/NK cells, absent thymic shadow

• Treatment: Bone marrow transplant, gene therapy, sterile isolation

Bruton Agammaglobulinemia

• Defect: BTK gene mutation (X-linked)

• Pathophysiology: B cells fail to mature

• Clinical: Recurrent bacterial/enteroviral infections after 6 months

• Diagnosis: Low levels of all Ig, absent B cells

• Treatment: IVIG, antibiotics

Common Variable Immunodeficiency (CVID)

• Defect: Multiple genetic causes

• Pathophysiology: Impaired B cell differentiation

• Clinical: Recurrent infections, autoimmune diseases

• Diagnosis: ↓IgG/IgA/IgM; normal B cell count

• Treatment: IVIG

Selective IgA Deficiency

• Defect: Unknown; most common primary immunodeficiency

• Pathophysiology: Failure to produce IgA

• Clinical: Recurrent mucosal infections, allergies, anaphylaxis to transfusions

• Diagnosis: ↓IgA, normal IgG/IgM

• Treatment: Avoid IgA-containing blood products

X-linked Hyper IgM Syndrome

• Defect: CD40L deficiency on T cells

• Pathophysiology: Defective class switching → ↑IgM, ↓other Ig

• Clinical: Recurrent infections with encapsulated organisms

• Diagnosis: ↑IgM, ↓IgG/IgA/IgE, normal B/T cell counts

• Treatment: IVIG, antibiotics

Complement Deficiencies

• Defects: C1–C9 or DAF/CD55

• Pathophysiology: Loss of opsonization (early) or MAC lysis (late)

• Clinical:

  • C1–C4 → SLE-like disease

  • C5–C9 → recurrent Neisseria infections

  • CD55 → paroxysmal nocturnal hemoglobinuria (PNH)

• Diagnosis: CH50, AH50, flow cytometry (PNH)

• Treatment: Eculizumab (PNH), vaccination

Hyper IgE Syndrome

• Defect: STAT3 mutation → ↓Th17

• Pathophysiology: Defective neutrophil chemotaxis

• Clinical: Coarse facies, retained primary teeth, eczema, fractures, recurrent staph abscesses

• Diagnosis: ↑IgE, eosinophilia, genetic testing

• Treatment: Prophylactic antibiotics, skin care

C1, C2, C4 Deficiencies (Classical Pathway)

• Defect: Deficiency in early classical pathway proteins (C1q, C1r, C1s, C2, or C4)

• Pathophysiology: Impaired clearance of immune complexes and apoptotic cells → persistent immune activation

• Clinical Manifestations:

  • ↑ Risk of Systemic Lupus Erythematosus (SLE)–like disease

  • Recurrent respiratory tract infections

  • Glomerulonephritis

• Diagnosis:

  • ↓ CH50 (classical pathway hemolytic activity)

  • Normal AH50 (alternative pathway intact)

  • Low levels of specific components (e.g., C2 or C4)

• Treatment: Monitor for autoimmune disease, vaccinate against encapsulated organisms, prompt antibiotic use

C3 Deficiency (Central Component)

• Defect: Deficiency of C3 (common to classical, lectin, and alternative pathways)

• Pathophysiology: Major opsonin loss → impaired phagocytosis and clearance of pathogens and immune complexes

• Clinical Manifestations:

  • Severe, recurrent pyogenic infections (e.g., Streptococcus pneumoniae, H. influenzae)

  • Immune complex–mediated diseases (e.g., membranoproliferative glomerulonephritis)

• Diagnosis:

  • ↓ C3 levels

  • ↓ CH50 and AH50

• Treatment: Aggressive infection control, vaccination, close monitoring

C5–C9 Deficiencies (Terminal Complement Components)

• Defect: Loss of terminal MAC (Membrane Attack Complex) formation

• Pathophysiology: Inability to lyse Neisseria via MAC → selective susceptibility

• Clinical Manifestations:

  • Recurrent infections by Neisseria species (especially N. meningitidis)

  • Usually not severe infections

• Diagnosis:

  • Normal C3 and early components

  • ↓ CH50 with normal AH50 (alternative intact but terminal deficient)

• Treatment:

  • Meningococcal vaccination (ACWY + B)

  • Prophylactic antibiotics (e.g., penicillin)

  • Immediate treatment of fever/infection

C1-Inhibitor Deficiency (Hereditary Angioedema)

• Defect: Quantitative or functional deficiency of C1-INH

• Pathophysiology: Uncontrolled activation of kallikrein → bradykinin ↑ → vascular permeability ↑

• Clinical Manifestations:

  • Recurrent non-pitting, non-pruritic angioedema (face, limbs, airway, GI tract)

  • No urticaria

• Diagnosis:

  • ↓ C4 during attacks

  • Low C1-INH function or level

• Treatment:

  • Acute: C1-INH concentrate, bradykinin receptor antagonists (e.g., icatibant)

  • Prophylaxis: androgens (e.g., danazol), antifibrinolytics

DAF (CD55) or CD59 Deficiency → Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Defect: Lack of GPI anchor → CD55/CD59 missing on RBCs

• Pathophysiology: RBCs are sensitive to complement → intravascular hemolysis

• Clinical Manifestations:

  • Hemolytic anemia, pancytopenia, thrombosis (especially abdominal veins)

  • Dark urine (especially in the morning)

• Diagnosis:

  • Flow cytometry for CD55/CD59 (best test)

  • Positive sucrose/acidified serum test (historical)

• Treatment:

  • Eculizumab (anti-C5 monoclonal antibody)

  • Transfusions, bone marrow transplant in severe cases

Type I – Immediate Hypersensitivity

• Mediators: IgE, mast cells, basophils

• Pathophysiology: Allergen cross-links IgE → degranulation → histamine, leukotrienes

• Clinical: Anaphylaxis, asthma, urticaria, allergic rhinitis

• Diagnosis: Skin prick test, serum IgE

• Treatment: Epinephrine, antihistamines

Type II – Antibody-Mediated Cytotoxicity

• Mediators: IgG/IgM against cell surface antigens

• Pathophysiology: Complement activation, ADCC

• Clinical: Hemolytic anemia, Goodpasture, Myasthenia gravis

• Diagnosis: Coombs test

• Treatment: Immunosuppressants

Type III – Immune Complex Hypersensitivity

• Mediators: Antigen-antibody (IgG) complexes

• Pathophysiology: Immune complexes deposit in tissues → inflammation

• Clinical: SLE, post-strep glomerulonephritis, serum sickness, Arthus reaction

• Diagnosis: ↓C3/C4, immune complex detection

• Treatment: Steroids, immunosuppressants

Type IV – Delayed-Type Hypersensitivity

• Mediators: T cells (CD4⁺ Th1 or CD8⁺ cytotoxic)

• Pathophysiology: T-cell mediated inflammation or cytotoxicity

• Clinical: Contact dermatitis, TB test, MS, type 1 diabetes

• Diagnosis: Patch test, biopsy

• Treatment: Avoid trigger, corticosteroids