3.2 Immunology

The immune system distinguishes self from non-self through two cooperating arms: the innate (rapid, nonspecific) and adaptive (slow, specific, memory-bearing) responses. The NABP FPGEE Content Outline expects you to apply these concepts to vaccination, hypersensitivity, transplantation, and immunosuppressive therapy.

Innate Immunity

Innate defenses act within minutes. Physical barriers (skin, mucociliary escalator, gastric pH) block entry. Pattern-recognition receptors such as the Toll-like receptors (TLRs) detect conserved pathogen-associated molecular patterns (PAMPs): TLR4 recognizes LPS, TLR3 recognizes double-stranded RNA, and TLR2 recognizes gram-positive lipoteichoic acid. Complement cascades (classical, alternative, and lectin pathways) opsonize pathogens, recruit neutrophils via C5a, and form the membrane attack complex (C5b through C9). Phagocytes — neutrophils (first responders, short-lived) and macrophages (tissue-resident, antigen-presenting) — engulf and kill via the respiratory burst and lysosomal enzymes. Natural killer (NK) cells kill virus-infected and tumor cells that downregulate MHC class I. The classic inflammatory signs — rubor, tumor, calor, dolor — describe the vascular and cellular response to injury.

Adaptive Immunity

Adaptive responses are antigen-specific and show memory. B lymphocytes mediate humoral immunity by differentiating into plasma cells that secrete antibodies. T lymphocytes mediate cell-mediated immunity. CD4 helper T cells coordinate responses via cytokines; CD8 cytotoxic T cells kill infected cells using perforin and granzymes.

Antigen presentation uses major histocompatibility complex (MHC) molecules. MHC class I presents intracellular peptides (viral, tumor) to CD8 T cells and is expressed on all nucleated cells. MHC class II presents extracellular peptides to CD4 T cells and is restricted to professional antigen-presenting cells (dendritic cells, macrophages, B cells).

Antibody Classes

Hypersensitivity Reactions

Autoimmunity

Autoimmune disease arises when self-tolerance fails. Systemic lupus erythematosus (SLE) features antinuclear antibodies and immune-complex deposition in kidneys and skin. Rheumatoid arthritis targets the synovium with anti-cyclic citrullinated peptide (anti-CCP) antibodies. Type 1 diabetes destroys pancreatic beta cells through a Type IV mechanism. Hashimoto's thyroiditis causes hypothyroidism via anti-thyroid peroxidase antibodies.

Immunization

Active immunity results from natural infection or vaccination and produces immunologic memory. Passive immunity transfers preformed antibodies (maternal IgG, rabies immune globulin, IVIG) and is short-lived. Vaccine types include live-attenuated (MMR, varicella, LAIV, yellow fever — contraindicated in significant immunocompromise), inactivated (IPV, rabies), subunit and recombinant (hepatitis B, HPV), toxoid (tetanus, diphtheria), and mRNA (COVID-19).

Cytokines and Immune Signaling

Cytokines are the chemical messengers that coordinate immune responses. Pro-inflammatory cytokines — IL-1, IL-6, and TNF-alpha — drive fever, acute-phase reactant synthesis (CRP, ferritin, fibrinogen), and systemic inflammation. IL-2 expands T cells after antigen recognition. IL-4 and IL-5 promote IgE class switching and eosinophil activation in allergy and parasite defense. IL-12 drives Th1 responses (intracellular pathogens), while IL-17 (from Th17 cells) recruits neutrophils for extracellular bacterial and fungal defense. Interferon-alpha inhibits viral replication; interferon-gamma activates macrophages. Therapeutic cytokine blockade has transformed autoimmune treatment: anti-TNF agents (infliximab, adalimumab, etanercept) treat rheumatoid arthritis, psoriasis, and inflammatory bowel disease but raise infection risk (reactivation of latent TB, fungal pneumonia). IL-6 blockade (tocilizumab) is used in giant cell arteritis and RA. IL-17 blockade (secukinumab) treats psoriasis and ankylosing spondylitis but can flare inflammatory bowel disease.

Immunodeficiency and Transplantation

Primary immunodeficiencies are rare inherited defects: X-linked agammaglobulinemia (absent B cells), common variable immunodeficiency (low antibody production), severe combined immunodeficiency (SCID) (defective T and B cells — fatal without bone marrow transplant), DiGeorge syndrome (thymic aplasia → T-cell deficiency), Wiskott-Aldrich (B and T cells with eczema and thrombocytopenia). Secondary immunodeficiency is far more common: HIV/AIDS (CD4 depletion), immunosuppressive drugs, malignancy, malnutrition, and splenectomy (encapsulated organism risk — vaccinate against pneumococcus, meningococcus, and H. influenzae b).

Transplantation matches donor and recipient through HLA typing and ABO compatibility. Solid organ transplants require lifelong immunosuppression, typically a calcineurin inhibitor plus an antimetabolite plus a corticosteroid. Hematopoietic stem cell transplantation carries graft-versus-host disease (GVHD) risk because donor T cells attack host tissues; prophylaxis uses methotrexate plus a calcineurin inhibitor. Rejection episodes are treated with high-dose corticosteroids, anti-thymocyte globulin, or plasmapheresis (antibody-mediated rejection).

Immunosuppressants

• Cyclosporine and tacrolimus — calcineurin inhibitors; block IL-2 transcription and T-cell activation. Monitor tacrolimus trough 5-15 ng/mL; nephrotoxicity and hypertension are shared adverse effects. Cyclosporine also causes gingival hyperplasia and hirsutism.
• Sirolimus (rapamycin) — mTOR inhibitor; blocks T-cell proliferation downstream of IL-2. Causes hyperlipidemia, impaired wound healing, and interstitial pneumonitis.
• Corticosteroids — suppress NF-kB-driven cytokine production and T-cell proliferation.
• Azathioprine — purine analog that blocks lymphocyte DNA synthesis.
• Mycophenolate — inhibits inosine monophosphate dehydrogenase, on which lymphocytes are especially dependent.
• Basiliximab — anti-CD25 monoclonal antibody for induction therapy.
• Rituximab — anti-CD20 monoclonal antibody that depletes B cells.

flowchart TD
    P[Pathogen] --> PAMP[PAMPs]
    PAMP --> TLR[TLRs]
    TLR --> Ph[Phagocyte]
    Ph --> APC[Antigen Presentation]
    APC --> MHCII[MHC II to CD4]
    APC --> MHCI[MHC I to CD8]
    MHCII --> TH[Helper T cells]
    TH --> B[B cells to Plasma cells to Antibodies]
    MHCI --> CTL[Cytotoxic T cells]
    P --> NK[NK cells]
    P --> Comp[Complement]