TB

Immunity

Innate Antiviral Action ─ Interferons

• Virus-infected host cells secrete interferons (IFNs) ⇒ act as “first messengers.”
• IFNs launch an intracellular signalling cascade identical in logic to other first-messenger systems, but the end-products are specialized antiviral proteins.
• Antiviral proteins block three key viral steps:
– Entry into adjacent cells.
– Insertion of viral DNA/RNA into host genome.
– Replication/assembly.
• Therapeutic drugs rarely mimic this; natural killer (NK) cells are the body’s “drug” that can directly lyse infected cells.

Overview of Adaptive Immunity

• Triggered only after antigen recognition; therefore slower but highly specific.
• Three sequential phases:

  1. Encounter & recognition of antigen.
  2. Activation (clonal expansion + differentiation).
  3. Attack / effector functions.
    • Principal adaptive cells (lymphocytes): B cells, Helper T (TH) cells, Cytotoxic T (TC) cells, and NK cells (borderline adaptive/innate).

Antigens & Autoimmunity

• Antigen = any molecular “name tag” that can be recognized by a lymphocyte receptor and provoke an immune response.
• Correct self–non-self discrimination is critical. Misrecognition → autoimmune disease (β-cell destruction in Type 1 Diabetes, rheumatoid arthritis, multiple sclerosis, etc.).

Lymphoid Organs & Lymphocyte Development

• Primary lymphoid organs:
– Bone marrow → B cells & NK cells mature here.
– Thymus → T-cell maturation (TH & TC).
• Secondary lymphoid organs: lymph nodes, spleen, tonsils, mucosal-associated lymphoid tissue (MALT).
– Lymph nodes reclaim fat-soluble molecules from interstitial fluid to venous blood and store quiescent lymphocytes in lymphatic nodules.
– Swollen “glands” during illness = lymph-node expansion while releasing stored cells.

Hemopoietic Lineage → Functional Lymphocytes

• Multipotent uncommitted hemopoietic stem cell (HSC) in marrow diverges:

  1. B-cell lineage: HSC → mature B cell → plasma cell → antibody secretion.
  2. T-cell lineage: HSC → immature T cell → thymic education →
    • Helper T (CD4⁺) – orchestrates responses.
    • Cytotoxic T (CD8⁺) – directly kills infected or malignant cells.
  3. NK-cell lineage – cytotoxic, non-antigen-specific.

Functional Division of Labor

• Helper T (TH):
– “Coach.” Releases cytokines (e.g., \text{IL-2}) that convert B cells → plasma cells and prime TC cells.
• Plasma cells (differentiated B):
– Secrete antibodies that act like runway signal wands guiding other effectors.
• Cytotoxic T (TC):
– Uses perforin/granzyme to destroy antigen-displaying host cells.
• NK cells:
– No antigen requirement; kill any cell lacking “healthy” self markers. Key in early viral defense & tumor surveillance.

Antibody (Immunoglobulin, Ig) Architecture

• Y-shaped heterotetramer: two identical light chains + two identical heavy chains.
• Variable regions at tips = antigen-binding sites.
• Constant (Fc) region docks onto:
– Phagocytes – Complement proteins – NK & TC cell receptors.
• Classes (IgG, IgM, IgA, IgE, IgD) differ in constant-region sequence and effector profile. (No memorization list required.)

Major Histocompatibility Complex (MHC) Tags

• Plasma-membrane “billboards” that display antigen fragments.
– Class I: on virtually all nucleated cells; present to CD8⁺ TC.
– Class II: on professional antigen-presenting cells (macrophage, dendritic cell, B cell); present to CD4⁺ TH.
• B cells do NOT interact with MHC for activation; NK cells activate without MHC.

Antigen Processing & Presentation → Helper T Activation

  1. APC (macrophage or B cell) engulfs pathogen (phagocytosis or receptor-mediated endocytosis).
  2. Pathogen fragmented in endosome/lysosome.
  3. Peptide fragment bound to Class II MHC.
  4. MHC-peptide complex trafficked to surface.
  5. T-cell receptor (TCR) on CD4⁺ binds the complex.
  6. Co-stimulation (“two-key” safety):
    • Non-antigenic protein–protein interaction.
    • Cytokine release (IL-1, TNF-α).
  7. TH cell proliferates and secretes \text{IL-2} ⇒ propagates full immune response.

Cytotoxic T Response to Virally Infected Cells

• Infected cell presents intracellular viral peptides on Class I MHC.
• CD8⁺ TC binds via TCR + co-receptor.
• Release perforin/granzyme → pore formation (“granulization”) analogous to complement MAC ⇒ osmotic lysis/apoptosis of target.

Natural Killer (NK) Cells

• Generated from marrow HSC; stored in lymph nodes.
• Activation independent of antigen or MHC; recognize cells lacking normal “self” markers.
• Important in early viral control & anti-tumor immunity.
• Hypo-function genetically linked to higher cancer susceptibility; hyper-release would cause indiscriminate tissue damage.

Immune Tolerance (Self-Acceptance)

• Established in fetal / early post-natal life by clonal deletion or inactivation of self-reactive lymphocytes.
• Prevents fetus from attacking trans-placental maternal antigens despite mixed cell populations.
• Breakdown of tolerance → autoimmunity.

Antibody-Mediated (Humoral) Immunity – Bacterial Example

  1. Bacterial breach (e.g., skin cut) introduces foreign antigen.
  2. Macrophage processes antigen → presents to TH.
  3. TH releases \text{IL-2} + cytokines.
  4. Antigen-bound B cell receives cytokine help → clonal expansion.
  5. Differentiation paths:
    • Plasma cells → secrete specific antibody.
    • Memory B cells → long-lived archive.
  6. Antibodies opsonize bacteria, activate complement, and flag targets for phagocytes & NK cells.

Memory Cells, Vaccination, Active vs Passive Immunity

• Primary response (first exposure): slow, low titer. Example: \approx 10 \text{ antibody units} after several weeks.
• Secondary response (re-exposure): rapid, amplified (≈ 3\times or more), owing to memory cells.
• Vaccination supplies harmless antigenic material → builds memory without disease.
• Active immunity = self-production of antibody/memory after antigen exposure or vaccine.
• Passive immunity = direct antibody transfer (maternal IgG across placenta, IgA in breast milk). Protective in first ≈6 months before infant immune maturation.

Antibody Effector Mechanisms

• Opsonization: Fc region binds phagocyte receptors ⇒ enhanced phagocytosis.
• Classical complement activation: antibody–antigen complex triggers \text{C3B} deposition ⇒ membrane attack complex (MAC).
• Antibody-dependent cellular cytotoxicity (ADCC): Fc interaction with NK/TC leading to target lysis.
• Buffering blood chemistry during massive pathogen lysis via binding free toxins/metabolic by-products.

Systemic (“Acute-Phase”) Responses & Modulating Factors

• Cytokines (IL-1, IL-6, TNF-α) induce:
– Fever – Anorexia – Somnolence – Hepatic synthesis of acute-phase proteins – Mobilization of amino acids, fatty acids – ↑ Cortisol → vasodilation & energy availability.
• Immunity weakened by: protein-calorie malnutrition, concurrent diseases, chronic stress, sleep deprivation; improved by moderate exercise, adequate rest.

Immunodeficiency Disorders

• Primary (genetic):
– SCID = absence of B, T (± NK) cells — extreme vulnerability.
• Acquired:
– HIV → AIDS: virus buds from CD4⁺ TH cells (electron micrograph shows budding vesicles) ⇒ gradual TH loss, immune collapse.
– Iatrogenic (e.g., chemotherapy) unintentionally suppresses immunity.

Harmful Immune Responses

• Hypersensitivity (Allergies): IgE-mediated.
– Immediate (minutes): bronchoconstriction, vasodilation, mucus — can produce systemic anaphylaxis.
– Late-phase (hours): eosinophil infiltration, tissue remodeling.
– Anaphylaxis treated with intramuscular epinephrine (EpiPen) ⇒ \alpha/\beta-adrenergic relaxation of airway smooth muscle (cautionary tale: accidental uninvolved injection triggers massive fight-or-flight).
• Autoimmune disease: mis-targeted self attack (Type 1 diabetes, MS, RA, myasthenia gravis).
• Rejection phenomena:
– Transfusion reaction when mismatched blood types transfused.
– Graft rejection (e.g., skin graft in burn victims).
• Excessive inflammatory responses can damage healthy tissue.

Mini-Glossary Snapshot (selected)

• Antigen – molecular marker provoking immunity