Master Immunology
for USMLE Step 1

Core Concepts

Immunology differentiates between **Innate Immunity** (first line, non-specific, rapid) and **Adaptive Immunity** (specific, memory, slower).
**Innate Cells:**

• **Neutrophils:** Phagocytose bacteria, first responders.
• **Macrophages:** Phagocytose, antigen presentation (MHC II), cytokine production.
• **Dendritic Cells:** Potent antigen-presenting cells (APCs) to T cells (MHC I/II), link innate and adaptive.
• **NK Cells:** Kill virus-infected and tumor cells without MHC.

• **B Cells:** Produce antibodies, differentiate into plasma cells, express MHC II.
• **T Cells:**
  • **Helper T Cells (CD4+):** Recognize antigens on MHC II; activate B cells, macrophages, and CD8+ T cells; produce cytokines (Th1, Th2, Th17, Treg).
  • **Cytotoxic T Lymphocytes (CD8+):** Recognize antigens on MHC I; kill virus-infected and tumor cells.

• **MHC I:** On all nucleated cells; presents endogenous antigens (e.g., viral); recognized by CD8+.
• **MHC II:** On APCs (dendritic cells, macrophages, B cells); presents exogenous antigens (e.g., bacteria); recognized by CD4+.

• **Pathways:** Classical (antibody-antigen complex), Alternative (microbial surfaces), Lectin (mannose-binding lectin).
• **Key Products:** C3b (opsonization), C3a/C5a (anaphylatoxins, inflammation), MAC (C5b-C9, cell lysis).

• **IgG:** Most abundant, crosses placenta, opsonization, complement activation.
• **IgA:** Mucosal immunity (tears, saliva, breast milk).
• **IgM:** Pentamer, first antibody produced in primary response, complement activation.
• **IgE:** Allergy, parasitic infections, mast cell/basophil activation.
• **IgD:** B cell receptor.

• **Type I (Anaphylactic):** IgE-mediated, mast cell degranulation (e.g., allergic asthma, anaphylaxis).
• **Type II (Cytotoxic):** IgG/IgM against cell surface antigens, complement, ADCC (e.g., hemolytic anemia).
• **Type III (Immune Complex):** IgG-antigen complexes deposit in tissues, complement, inflammation (e.g., SLE, serum sickness).
• **Type IV (Delayed-Type):** T-cell mediated (CD4+ or CD8+), takes 24-72 hours (e.g., contact dermatitis, TB skin test).

Clinical Presentation

• **Primary Immunodeficiencies:** Recurrent, severe, or opportunistic infections.
• **SCID (Severe Combined Immunodeficiency):** Failure to thrive, recurrent severe infections (viral, fungal, bacterial), absent thymus.
• **X-linked Agammaglobulinemia (Bruton's):** Recurrent bacterial infections (e.g., *Streptococcus pneumoniae*, *Haemophilus influenzae*) starting ~6 months, absent B cells/germinal centers.
• **DiGeorge Syndrome:** T-cell deficiency (thymic aplasia), hypocalcemia (parathyroid aplasia), cardiac defects (conotruncal).
• **Chronic Granulomatous Disease (CGD):** Recurrent infections with catalase-positive organisms (*Staph aureus*, *Aspergillus*) due to impaired phagocyte oxidative burst.
• **Common Variable Immunodeficiency (CVID):** Recurrent sinopulmonary infections, enteroviral infections, increased autoimmune disease risk; normal B cell numbers but decreased Ig.
• **Selective IgA Deficiency:** Most common primary immunodeficiency; often asymptomatic, but can have recurrent sinopulmonary/GI infections, anaphylaxis to IgA blood products.
• **Leukocyte Adhesion Deficiency (LAD):** Recurrent bacterial infections, impaired wound healing, omphalitis, lack of pus formation, persistent leukocytosis.
• **Autoimmune Diseases:** Symptoms vary by disease (e.g., butterfly rash in SLE, joint pain in RA, dry eyes/mouth in Sjögren's). Often systemic inflammation, fatigue.
• **Graft-versus-Host Disease (GVHD):** Transplanted T cells attack host tissues (skin rash, liver dysfunction, GI upset); common in bone marrow transplant.

Diagnosis (Gold Standard)

• **Immunodeficiencies:**
  • **Flow cytometry:** Quantifies lymphocyte subsets (T cells, B cells, NK cells) and surface markers (e.g., CD3, CD4, CD8, CD19).
  • **Quantitative Immunoglobulins:** Measures IgG, IgA, IgM levels.
  • **Specific Antibody Responses:** Measure antibody titers post-vaccination (e.g., tetanus, diphtheria, pneumococcal).
  • **NBT/DHR test:** For CGD (impaired oxidative burst).
  • **Genetic testing:** Confirmatory for many specific immunodeficiencies.
• **Autoimmune Diseases:**
  • **Autoantibody detection:** ANA (SLE, non-specific), anti-dsDNA/anti-Smith (SLE specific), RF/anti-CCP (RA), ANCA (vasculitis), anti-TSH receptor (Grave's).
  • **Biopsy:** For specific organ involvement.
• **Allergies/Hypersensitivity:**
  • **Skin prick test:** For Type I.
  • **Specific IgE levels (RAST test):** For Type I.
  • **Patch test:** For Type IV (contact dermatitis).
• **Transplant Rejection:** **Biopsy** of the transplanted organ.

Management (First Line)

• **Primary Immunodeficiencies:**
  • **Intravenous Immunoglobulin (IVIG):** For antibody deficiencies (e.g., XLA, CVID).
  • **Prophylactic Antibiotics:** To prevent recurrent infections.
  • **Hematopoietic Stem Cell Transplant (HSCT):** Curative for SCID, CGD.
  • **PEG-ADA:** For ADA-SCID.
• **Autoimmune Diseases:**
  • **NSAIDs:** For pain and inflammation.
  • **Corticosteroids:** Potent anti-inflammatory and immunosuppressants.
  • **Disease-Modifying Antirheumatic Drugs (DMARDs):** Methotrexate, sulfasalazine, hydroxychloroquine.
  • **Biologic Agents:** TNF-alpha inhibitors (infliximab, etanercept), rituximab (anti-CD20).
  • **Immunosuppressants:** Azathioprine, mycophenolate mofetil, cyclophosphamide.
• **Allergies:**
  • **Antihistamines:** For mild symptoms.
  • **Corticosteroids:** For more severe reactions.
  • **Epinephrine:** For anaphylaxis.
• **Transplant Rejection:** **Immunosuppressive agents** (e.g., calcineurin inhibitors like tacrolimus/cyclosporine, corticosteroids, antimetabolites like mycophenolate mofetil).