Classification of Immunity

1. Innate Immunity (Natural / Native Immunity)

• Present before any infection occurs; provides defense within hours of exposure
• Does not adapt or improve with re-exposure (limited memory)
• Recognizes broad molecular patterns shared by groups of microbes (PAMPs) via germline-encoded receptors
• Components:
  • Physical/chemical barriers: skin, mucosal epithelia, antimicrobial peptides
  • Cellular: phagocytes (macrophages, neutrophils), dendritic cells, NK cells, mast cells, innate lymphoid cells (ILCs)
  • Soluble: complement, lectins, acute-phase proteins
• Key features: low specificity, low diversity, rapid response

2. Adaptive Immunity (Specific / Acquired Immunity)

• Develops over days in response to infection; increases in magnitude and quality with each successive exposure
• Recognizes a vast array of antigens through somatically recombined receptors
• Has immunological memory
• Subdivided into:

• Key features: high specificity, high diversity (somatic recombination), memory, self-tolerance

T-Cell Immunity

Antigen Presentation & T-Cell Activation

• MHC class I proteins present antigens to cytotoxic (CD8+) T cells
• MHC class II proteins present antigens to helper (CD4+) T cells and regulatory T cells
• T-cell receptors (TCRs) on the T-cell surface bind the peptide-MHC complex; each T cell has up to 100,000 receptor sites
• Cell adhesion proteins are required to hold the T cell to the APC long enough for activation to occur

Types of T Cells

1. T-Helper Cells (CD4+) - >75% of all T cells

2. Cytotoxic T Cells (CD8+)

• Recognize antigen on MHC class I (expressed on all nucleated cells)
• Directly kill virus-infected cells, tumor cells, and transplanted foreign cells
• Kill via perforins and granzymes or Fas-FasL interaction

3. Regulatory T Cells (Tregs / Suppressor T Cells)

• Suppress excessive immune activation
• Maintain self-tolerance; prevent autoimmunity

T-Cell Effector Release and Memory

B-Cell and T-Cell Coactivation

Step-by-Step Mechanism

1. BCR signal (Signal 1): The B-cell antigen receptor (BCR/surface Ig) binds antigen. This initiates intracellular signaling and also internalizes the antigen. The antigen is processed and its peptide fragments are returned to the cell surface bound to MHC class II molecules.
2. T-cell recognition: An antigen-specific CD4+ TFH (follicular helper T) cell that has already been activated by the same pathogen recognizes the peptide-MHC II complex on the B-cell surface.
3. Co-stimulatory signal (Signal 2 - CD40-CD40L interaction): The T cell expresses CD40 ligand (CD40L / CD154) which binds CD40 on the B cell. This activates:
   • The canonical NF-κB signaling pathway (via IKK)
   • The non-canonical NF-κB pathway (via NIK/NF-κB-inducing kinase)
   • Expression of anti-apoptotic proteins (e.g., Mcl-1), promoting B-cell survival
4. Cytokine signals: The T cell secretes IL-21 (activates STAT3, enhancing B-cell proliferation and plasma cell differentiation), plus IL-4, IL-6, IL-2, TGF-β, and IFN-γ - these regulate isotype switching (IgM → IgG, IgA, IgE).
5. Outcome: Activated B cells proliferate, enter germinal centers, undergo somatic hypermutation (affinity maturation), and differentiate into:
   • Plasma cells - long-lived antibody-secreting factories
   • Memory B cells - rapid responders upon re-exposure

Thymus-Independent (TI) Antigens

Note on AIDS (Acquired Immunodeficiency Syndrome)

The Virus

Mechanism of CD4+ T-Cell Infection

1. Entry: HIV envelope glycoprotein gp120 binds CD4 molecules on helper T cells, forming a CD4-gp120 complex. This exposes gp41, which anchors the virus into the T-cell membrane. CCR5 (C-C chemokine receptor type 5) acts as a major co-receptor for gp120 binding.
2. Fusion & injection: The viral envelope fuses with the T-cell membrane, injecting viral RNA + reverse transcriptase into the cytoplasm.
3. Reverse transcription: Viral RNA is reverse-transcribed into double-stranded proviral DNA.
4. Integration: Viral integrase incorporates proviral DNA into the host genome permanently.
5. Replication: New viral particles are produced and bud off to infect more helper T cells.

Immune Consequences

• The immune system initially responds by generating CD8+ cytotoxic T cells and antibodies against HIV
• But CD8+ T cells kill the HIV-infected CD4+ T cells, progressively reducing their numbers
• The CD4+ T-cell count is used clinically as a marker of disease progression (AIDS defined as CD4 <200 cells/μL)
• As CD4+ T cells are depleted, the entire immune system collapses - B cells lose T-cell help, cytotoxic T cells lose T-helper support, macrophage activation fails
• Patients die of opportunistic infections (PCP, CMV, Toxoplasma, cryptococcal meningitis, MAC) and AIDS-defining cancers (Kaposi sarcoma, NHL)

Treatment

• Antiretroviral therapy (ART): Combination of multiple drug classes to suppress viral replication:
  • NRTIs (nucleoside reverse transcriptase inhibitors, e.g., AZT/zidovudine - the first drug used)
  • NNRTIs (non-nucleoside reverse transcriptase inhibitors)
  • Protease inhibitors (block viral protease)
  • Integrase strand transfer inhibitors (prevent proviral DNA integration)
• ART advantages over monotherapy: synergistic effects, reduced side effects, and reduced drug resistance
• ART does not cure HIV but can suppress viral load to undetectable levels, allowing near-normal CD4 counts and life expectancy