Chapter 22 – Immune System Review

Functions of the Immune System

• Protect the body from infectious agents (pathogens), abnormal “self” cells (e.g., cancer), and environmental substances (pollens, toxins).
• Remove dead/damaged cells and cellular debris to maintain tissue homeostasis.
• Surveillance: continuously monitor for antigenic change.
• Coordinate repair of injured tissues (e.g., via inflammation, growth factors).
• Establish immunologic memory – a faster, stronger response upon re-exposure.

Interaction of the Immune & Lymphatic Systems

• Lymphatic vessels drain interstitial fluid → return it to blood, preventing edema and constantly sampling tissues for antigens.
• Lymph nodes, spleen, MALT, tonsils = secondary lymphatic structures where lymphocytes are “educated,” activated, and clonal-expanded.
• Transport highway: Antigen-presenting cells (APCs) and lymphocytes migrate through lymph/blood ("recirculation") ensuring body-wide protection.

22.1 Diseases Caused by Infectious Agents

Key Definitions

• Infectious agent = any organism capable of causing disease.
• Pathogenic agent = infectious agent with the ability to overcome host defenses and cause pathology.

Five Major Classes of Pathogens ( + common examples )

• Bacteria – prokaryotes; e.g., Mycobacterium tuberculosis, Streptococcus pneumoniae.
• Viruses – obligate intracellular; e.g., Influenza virus, HIV, SARS-CoV-2.
• Fungi – eukaryotic; e.g., Candida albicans, Aspergillus spp.
• Protozoa – single-celled eukaryotes; e.g., Plasmodium (malaria), Giardia.
• Multicellular parasites – helminths; e.g., tapeworm (Taenia), hookworm.
(• Prions are sometimes listed separately – misfolded proteins, e.g., Creutzfeldt-Jakob disease.)

22.2 Overview of the Immune System

Cytokines

• Small soluble proteins that serve as chemical messengers; released by almost every immune/other cell.
• Act in autocrine, paracrine, or endocrine fashion to coordinate immunity, hematopoiesis, and inflammation.
• Key families: interleukins (IL-1…IL-37), interferons (IFNs), tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), chemokines.

Innate (Nonspecific) vs Adaptive (Specific) Immunity

22.3 Innate Immunity

General Characteristics

• Present at birth; first to respond.
• Responds the same way to all pathogens on every encounter.
• No need for prior exposure.

First vs Second Line of Defense

• First line = barriers that block entry.
• Second line = internal innate mechanisms activated once the pathogen is inside tissues/blood.

Goals

• Barriers: prevent colonization.
• Second line: quickly contain, slow spread, and prepare for adaptive response.

Physical, Chemical, & Biological Barriers

• Skin – keratinized stratified epithelium, tight junctions, sloughing cells.
• Mucous membranes – line GI, respiratory, GU tracts; mucus traps microbes; cilia propel.
• Chemical – sweat (high salt, lysozyme), sebum (acidic, antibacterial), gastric acid (pH ≈ 1), tears & saliva (lysozyme, IgA), vaginal flora (lactic acid).
• Biological – resident microbiota compete for space/nutrients, secrete bacteriocins.

Innate Immune Cells & Their Functions

• Neutrophils – fastest phagocytes; form extracellular traps (NETs); predominant in acute bacterial infection (↑ neutrophilia).
• Macrophages – derived from monocytes; long-lived; phagocytosis, antigen presentation, produce IL-1, TNF-α.
• Dendritic cells – “sentinels” in skin (Langerhans) & mucosa; best APCs; link innate → adaptive.
• Basophils – circulate; release histamine, heparin; allergy and parasite defense.
• Mast cells – tissue-resident basophil analogs; trigger inflammation via histamine, eicosanoids.
• Eosinophils – fight parasites; participate in allergies; release major basic protein; undertake antibody-dependent cellular cytotoxicity (ADCC).
• Natural Killer (NK) cells – lymphoid lineage; detect cells lacking \text{MHC I}; induce apoptosis using perforin/granzymes; secrete IFN-γ.

Antimicrobial Proteins

• Interferons (IFN-α, IFN-β from virally infected cells; IFN-γ mainly from NK & T cells)
◦ Bind nearby cells → activate antiviral genes (protein kinase R, RNase L) → block viral replication.
◦ Enhance MHC I expression & activate NK/macrophage activity.
• Complement System (≈ 30 plasma proteins C1–C9, B, D, P)
◦ Best against bacteria & enveloped viruses.
◦ Activated via classical, lectin, or alternative pathways ➔ common terminal pathway (C3 → C3b/C3a … C5b-9).
◦ Three major defense mechanisms:
▸ Opsonization: C3b coats microbe → easier phagocytosis.
▸ Cytolysis: C5b–C9 form membrane attack complex (MAC).
▸ Inflammation: C3a, C5a act as anaphylatoxins (mast-cell degranulation) & chemotaxins.

Inflammation

• Definition: Local, protective tissue response to injury or infection designed to eliminate cause, remove debris, and initiate repair.
• Events (minutes → days):
1. Release of inflammatory mediators (histamine, eicosanoids, cytokines, complement).
2. Vascular changes – vasodilation ↑ blood flow; ↑ capillary permeability; endothelial production of CAMs → leukocyte adhesion.
3. Recruitment of leukocytes – margination → diapedesis → chemotaxis.
4. Phagocytosis & removal; plasma proteins (fibrinogen, complement) enter tissue; exudate forms.
• Benefits – isolates microbes, brings immune cells & nutrients, dilutes toxins, sets stage for repair.
• Cardinal signs (with causes):
• Redness (rubor) – \uparrow blood flow.
• Heat (calor) – warm blood.
• Swelling (tumor) – fluid exudation.
• Pain (dolor) – bradykinin, prostaglandins sensitize nociceptors.
• Loss of function – protective, from pain & swelling.

Fever (Pyrexia)

• Definition: Body temperature > 38 ^{\circ}\text{C} ( > 100.4 ^{\circ}\text{F} ).
• Mechanism: Pyrogens (exogenous LPS, endogenous IL-1, IL-6, TNF-α) reset hypothalamic set-point via PGE2 ⇒ shivering/vasoconstriction raise temperature.
• Benefits: Inhibits microbial replication, accelerates metabolism, promotes tissue repair, enhances interferon activity.
• Risks (> 40 ^{\circ}\text{C}): protein denaturation, seizures (children), delirium, dehydration; > 43 ^{\circ}\text{C} = fatal.

22.4 Adaptive Immunity: Introduction

Defining Characteristics

• Specificity, inducibility, clonality, memory, and self-tolerance.
• Divided into humoral (antibody-mediated) and cell-mediated branches.

Humoral vs Cell-Mediated

• Humoral – B-cells → plasma cells → antibodies that circulate in body fluids; best vs extracellular microbes/toxins.
• Cell-Mediated – T cells directly kill infected cells or orchestrate responses; best vs intracellular microbes, cancer, graft tissue.

Antigens

• Any substance that triggers an adaptive immune response.
• Foreign (non-self) vs Self (tolerated in health). Autoimmunity = self recognized as foreign.
• Immunogenicity = ability to provoke immune response.
• Haptens = small molecules (< 10 kDa) not immunogenic alone but become so when bound to carrier protein (e.g., penicillin-albumin).

Lymphocyte Receptors

• T-cell receptor (TCR) – αβ heterodimer; recognizes antigen only when presented on MHC.
• B-cell receptor (BCR) – membrane-bound antibody (IgD/IgM) that directly binds native antigen.

Lymphocyte Subtypes & APCs

• T-lymphocytes: CD4+ helper (Th), CD8+ cytotoxic (Tc), CD4+CD25+ regulatory (T_reg).
• APCs: dendritic cells, macrophages, B-cells (all express \text{MHC II}).

Relationship – APCs, MHC, & T Cells

• APCs process antigen → load peptide onto MHC → migrate to lymph node → present to T cells.

MHC Classes

• MHC I – all nucleated cells; present endogenous peptides; recognized by CD8+ Tc. • MHC II – APCs; present exogenous peptides; recognized by CD4+ Th.

Importance in Transplantation

• MHCs = HLAs; differing alleles → graft seen as foreign.
• Immunosuppressive drugs (cyclosporine, tacrolimus, corticosteroids): reduce rejection by dampening T cells but ↑ infection & cancer risk.
• Rejection mediated by CD8+ Tc, CD4+ Th, NK cells, antibodies.

Life of a Lymphocyte (3 Main Events)

1. Formation & maturation (primary lymphatic structures).

2. Activation (exposure to antigen in secondary structures).

3. Effector response (at infection site or in blood).

22.5 Formation & Selection in Primary Structures

• Production: hematopoietic stem cells (HSCs) in red bone marrow.
• Maturation:
• B-cells – bone marrow.
• T-cells – thymus (cortex → medulla).

Need to Mature

• Develop antigen-specific receptors (immunocompetence).
• Eliminate self-reactive clones (self-tolerance).

Positive vs Negative Selection (T Cells)

• Positive: Can T cell bind self-MHC? YES → survive. NO → apoptosis.
• Negative: Does TCR bind self-antigen strongly? YES → apoptosis (to prevent autoimmunity). Moderate/weak → survive.

• Outcome: surviving cells become naïve immunocompetent T or B cells.
• After maturation: migrate via blood to lymph nodes, spleen, MALT awaiting activation.
• Naïve = has receptor but has never encountered its specific antigen.

22.6 Activation & Clonal Selection

• Antigen recognition + costimulation (second signal) activate lymphocyte.
• Activated cell undergoes clonal expansion → many identical effector + memory cells.
• Differentiation:
• CD4+ → different T_h subsets (Th1, Th2, Th17) + memory Th.
• CD8+ → cytotoxic Tc + memory Tc.
• B-cell → plasma cell (antibody factory) + memory B.
• Proliferation ensures enough soldiers; continuous recirculation increases chance to meet antigen anywhere in body.

22.7 Effector Responses at Infection Site

• Helper T (Th): secrete cytokines (IL-2, IFN-γ) ⇒ activate B cells, Tc, macrophages; coordinate entire response.
• Cytotoxic T (Tc): release perforin + granzymes → apoptosis of infected/cancerous cells; produce Fas-ligand.
• B-cells/Plasma cells: secrete up to 2000 antibody molecules/sec for ≈ 4 days then die.
• Memory cells: long-lived; mount secondary responses.
• Regulatory T (T_reg): suppress immune response, prevent autoimmunity (IL-10, TGF-β).

22.8 Immunoglobulins (Antibodies)

Antibody Defensive Mechanisms

• Neutralization – cover active site of toxin/virus.
• Agglutination – cross-link cells (IgM).
• Precipitation – cross-link soluble antigens.
• Opsonization – Fc enables phagocytosis.
• Complement activation (classical) – C1 binds Fc.
• ADCC – recruit NK/eosinophils via Fcγ/ Fcε.

Hypersensitivities

• Type I (acute) – IgE mediated (e.g., hay fever, asthma, anaphylaxis).
◦ Initial exposure → IgE → mast-cell sensitization.
◦ Re-exposure → massive degranulation → histamine → vasodilation, bronchoconstriction, edema.
◦ Anaphylactic shock: systemic vasodilation ↓ BP, airway obstruction, possible death.
◦ EpiPen (epinephrine) – α₁ vasoconstriction ↑ BP, β₂ bronchodilation.
• Type IV (delayed, cell-mediated) – T cells (e.g., contact dermatitis – poison ivy, TB skin test, graft rejection).

22.9 Immunologic Memory & Immunity

Primary vs Secondary Response

• Primary: lag of ~3 days, IgM peaks then falls, IgG later but lower.
• Secondary: memory cells respond within hours; high & prolonged IgG (sometimes IgA/IgE); basis of vaccine efficacy.

Active vs Passive Immunity

Vaccines

• Contain attenuated, inactivated, subunit, toxoid, or mRNA antigens.
• Stimulate primary response without causing disease; develop memory B & T cells.
• Herd immunity: when > \sim 85-95\% of population immune → interrupt transmission, protecting vulnerable.

Immunodeficiency

• Congenital (primary) – genetic; e.g., SCID (defective IL-2Rγ chain) → no functional B/T cells; requires bone marrow transplant or gene therapy.
• Acquired (secondary) – e.g., HIV infection.
◦ HIV targets CD4+ T cells (via gp120 – CD4 + CCR5/CXCR4) → progressive loss → opportunistic infections & cancers.

Ethical/Practical Implications: vaccination programs, transplant immunosuppression balancing rejection vs infection risk, antibiotic stewardship to reduce resistance, and recognition of autoimmune/allergic conditions for quality of life.