Pathos #2: Immunity and Neoplastic Disease — Comprehensive Notes

Immunity and Neoplastic Disease — Comprehensive Notes

Immunity: Overview

• Immunity is a broad, cumulative topic tying together many concepts throughout the course.

• Two major arms: innate immunity (born with, immediate, nonspecific) and adaptive immunity (specific, long-lasting, memory).

• Innate immunity forms the body’s first line of defense against pathogens (bacteria, viruses, fungi).

• Adaptive immunity involves T cells and B cells, can develop memory, and is more specific.

• Innate immunity supports and activates adaptive immunity.

• Inflammation and fever are intertwined with both innate and, to some extent, adaptive responses.

• Pathophysiology focus: link between immunity and disease, including immunodeficiency and cancer (neoplasia).

Innate Immunity

• Innate immunity provides immediate, nonspecific protection; it’s always on from birth.

• Barriers and defenses include physical barriers, cellular defenses, and chemical defenses.

• Barrier: skin is the most obvious innate barrier; the outermost skin layer is composed of dead cells and is continually replenished.

• Mucous membranes line entry points (respiratory and digestive tracts); mucus traps pathogens and can aid in expulsion.

• Cellular defenses: phagocytic cells (neutrophils, macrophages) patrol tissues and engulf pathogens (Pac-Man analogy for engulfment).

• Natural killer (NK) cells are specialized immune cells that identify and destroy infected or abnormal host cells (e.g., virus-infected or cancer cells).

• Chemical defenses: antimicrobial peptides; the complement system—a group of circulating proteins that promote opsonization and inflammation.

• Complement pathways: classical pathway (antigen + antibody) and alternative pathway; both can lead to coating of pathogens and recruitment of immune cells.

• Complement-mediated lysis via the membrane attack complex (MAC) can cause osmolysis (cell lysis) of the target.

• Opsonization: marking pathogens with antibodies or complement to enhance phagocytosis.

• Innate antimicrobial peptides disrupt pathogens by attacking membranes.

• Inflammation triggers: chemical signals increase blood flow and recruit immune cells; fever is a component that can inhibit some pathogens.

• Innate immunity and inflammation can trigger adaptive responses by presenting antigens via APCs.

• Role of antigen-presenting cells (APCs): dendritic cells, macrophages, and B cells process and present antigens to T cells via MHC.

• Classification limitations of innate immunity: lacks specificity and memory; pathogens may evade innate responses; some infections require adaptive immunity for full clearance.

Adaptive Immunity

• Adaptive immunity provides more specific, long-lasting protection and involves T cells and B cells; memory cells enable faster responses on re-exposure.

• Interaction between innate and adaptive immunity: innate signals guide adaptive responses (e.g., through APCs presenting antigens).

• T cells (CD4+, helper T cells; CD8+, cytotoxic T cells) and B cells (humoral immunity) are central players.

• T cells and NK cells originate from early innate-like lineages but acquire memory with adaptive signaling.

• Humoral immunity (antibody-mediated) vs cell-mediated immunity (T cell–mediated).

Humoral Immunity (Antibody-Mediated Immunity)

• Humoral immunity is antibody-mediated and is particularly effective against bacteria and bacterial toxins.

• B cells: central players; activated B cells differentiate into plasma cells that secrete antibodies (immunoglobulins).

• Antibodies neutralize antigens by various mechanisms: prevent attachment to host cells, mark for destruction (opsonization), and neutralize toxins.

• Antibodies can also act as antigen receptors on B cells before activation.

• Antibody structure: heavy chain (large polypeptide) + light chain (smaller polypeptide); each antibody has a unique antigen-binding site; heavy chain contains the variable region that encodes antigen specificity.

• Major immunoglobulins (classes):

  • IgG (IgG, principal antibody produced in response to many pathogens; involved in classical complement pathway and systemic immunity).

  • IgM (pentameric form; high avidity; efficient at neutralizing fungi; early in primary responses; part of the classical pathway).

  • IgA (found in mucosal tissues; exists as a dimer; provides mucosal protection in respiratory and gastrointestinal tracts).

  • IgE (involved in allergies and defense against parasitic infections; present in low levels in blood; mediates allergic reactions via mast cell/basophil degranulation).

  • IgD (present on B cell surfaces; function less well defined; found across species; typically low levels in blood).

• Antibody structural notes:

  • Heavy chain: large polypeptide with highly variable regions; determines antigen binding specificity.

  • Light chain: smaller polypeptide; contributes to antigen binding site.

  • Antigen-binding site formed by variable regions of heavy and light chains; often depicted with specific shape complementary to antigen.

• Immunoglobulin class shapes:

  • IgG: monomeric form; principal systemic antibody.

  • IgM: pentameric; high valence; strong in initial response to pathogens and binding pathogens like fungi.

  • IgA: dimer; secreted into mucosal surfaces and breast milk.

  • IgE: triggers allergic responses and defense against parasites.

  • IgD: membrane-bound; role in B cell activation and early development.

Antigen Presentation and Lymphocyte Activation

• Antigen processing and presentation are essential for initiating adaptive responses.

• APCs (e.g., dendritic cells, macrophages, B cells) engulf pathogens, process antigens into smaller fragments, and present them on MHC molecules.

• MHC molecules:

  • MHC class I presents to CD8+ cytotoxic T cells (intracellular antigens).

  • MHC class II presents to CD4+ helper T cells (extracellular antigens captured by APCs).

• T cell receptors (TCRs) recognize antigens only when presented by MHC:

  • CD4+ T cells interact with MHC II–bound antigens.

  • CD8+ T cells interact with MHC I–bound antigens.

• B cells can function as APCs and, when activated, proliferate to form plasma cells that secrete antibodies.

• T helper (CD4+) cells regulate the immune response and assist other immune cells, including B cells.

• Cytotoxic T (CD8+) cells destroy infected host cells and abnormal cells; critical for intracellular pathogens and transplant rejection.

• Activation sequence (simplified): APC engulfs antigen → antigen processed and displayed on MHC → TCRs of T cells recognize antigen-MHC complexes → co-stimulation signals reinforce activation → B cell activation and antibody production occur with T cell help.

• Immunological signaling: chemokines and other cytokines coordinate cell recruitment and activation.

Lag Phase and Immune Memory

• Primary immune response includes a lag phase (often about a week or longer) before detectable immune activity, due to activation and clonal expansion of lymphocytes.

• After exposure, lymphoid cells develop memory of the antigen (sensitization), leading to a faster and stronger response on re-exposure.

• T cell memory vs B cell memory: B cells can directly bind whole antigens; T cells require antigen presentation by APCs and MHC for activation.

• B cells generate plasma cells that secrete antibodies; memory B cells provide rapid antibody production upon re-exposure.

Immune Response Genes and HLAs

• Immune response genes include human leukocyte antigen (HLA) complexes located on chromosome 6.

• HLAs regulate immune cell proliferation and function (T and B cells), influencing resistance to infections and tumors, and susceptibility to autoimmune disease.

• HLAs are linked to variations in infection susceptibility, tumor resistance, and risk of autoimmunity; exact mechanisms remain an active area of research.

Allergies and Hypersensitivity

• Hypersensitivity reactions: exaggerated or abnormal immune responses to antigens; not all immune responses are harmful, and some individuals with allergies still have protective immunity to other antigens.

• Types of hypersensitivity (ACID mnemonic):

  • Type I: IgE-mediated, immediate; allergic reactions and anaphylaxis; examples: bee stings, latex, penicillin; mediators include histamine; treated with antihistamines.

  • Type II: Cytotoxic; antibodies (often IgG/IgM) bind to cell or tissue antigens and activate complement → lysis or membrane damage (e.g., autoimmune hemolytic anemia).

  • Type III: Immune complex–mediated; IgG/IgM–antigen complexes deposit in tissues, activate complement, cause inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus).

  • Type IV: Delayed or cell-mediated; sensitized T cells react on re-exposure, activating macrophages and causing inflammation (e.g., tuberculosis, contact dermatitis; chronic graft rejection).

• Allergic sensitization process:

  • First exposure: APC presents allergen fragment to T helper cells; B cells produce IgE; IgE binds to mast cells/basophils.

  • Re-exposure: IgE-mediated degranulation releases histamines and other mediators, causing symptoms; antihistamines mitigate symptoms by lowering mediator levels.

• Cross-reactivity and common links: latex allergies often co-occur with shellfish allergies; drug allergies (e.g., penicillin) common.

Autoimmune Diseases and Tolerance

• Immune tolerance to self-antigens should prevent autoimmunity; breakdown leads to autoimmune diseases.

• Mechanisms contributing to autoimmunity (briefly):

  • Altered self antigens causing neoantigens.

  • Cross-reactive antibodies that react with self-antigens.

  • Regulatory T cell (Treg) dysfunction, leading to loss of immune control.

• Examples of autoimmune diseases mentioned: rheumatoid arthritis, psoriasis, multiple sclerosis, type 1 diabetes, Crohn’s disease, ulcerative colitis, among others.

• Practical implications: autoimmune diseases involve immune dysregulation; management often includes immune suppression and lifestyle considerations.

Vaccines, Immunity, and Public Health Context

• Vaccines prime the immune system to recognize pathogens and mount quicker, stronger responses upon exposure.

• mRNA vaccines are discussed as a way to prepare the immune system to recognize pathogens (e.g., coronavirus) without infection.

• Immunity debt vs immunity theft debate:

  • Immunity debt (no evidence) claims lockdowns caused increased susceptibility due to lack of exposure; author argues there is no evidence for a debt; rather, COVID may dysregulate innate immunity.

  • Immunity theft (informal term) suggests COVID infection may “steal” or dampen immune response; conflates with global observations that vaccines work and that exposure affects immunity in complex ways.

• Vaccination advocacy: vaccines promote protective antibodies and reduce disease burden; mRNA vaccines are not dangerous; concerns about mRNA content are unfounded according to cited context.

• Overall: immune response genes influence susceptibility; vaccines strengthen population immunity; lifestyle and nutrition support general health but do not “boost” immunity in a simple, guaranteed way.

Immune Suppression and Clinical Management

• Immune suppression is used to dampen excessive immune responses, prevent transplant rejection, and manage autoimmune diseases.

• Methods include:

  • Immunosuppressive drugs (e.g., corticosteroids; calcineurin inhibitors like cyclosporine; antimetabolites such as methotrexate).

  • Radiation to suppress immune activity in specific tissues.

  • Gamma globulin preparations to provide passive immunity against specific antigens.

• Outcomes vary; some individuals respond better than others; balancing suppression to avoid infection while preventing immune-mediated damage is key.

• Clinical cautions: organ transplant rejection remains a risk; sometimes transplanted organs must be removed if rejection is uncontrolled.

Autoimmune Diseases: Mechanisms and Examples (Expanded)

• Mechanisms include:

  • Self antigen alteration creating new antigenicity.

  • Cross-reactivity of antibodies with similar self antigens.

  • Regulatory T cell (Treg) dysfunction leading to poor immune control.

• Examples listed:

  • Rheumatoid arthritis

  • Psoriasis

  • Multiple sclerosis

  • Type 1 diabetes (insulin-dependent) – autoimmune destruction of pancreatic beta cells

  • Crohn’s disease and ulcerative colitis (gastrointestinal tract)

• Note: Many autoimmune diseases have multifactorial etiologies with genetic and environmental components; the field is active with ongoing research.

Neoplastic Disease (Cancer): Overview

• Cancer is a broad, multifactorial disease characterized by uncontrolled cell growth and the potential to invade and metastasize.

• Classification and nomenclature:

  • Benign tumors: localized, well circumscribed, usually slow-growing; noninvasive; can compress structures but do not invade surrounding tissues.

  • Malignant tumors: cancerous; invade adjacent tissues and can metastasize via blood or lymphatic routes; show marked cellular variability and loss of normal architecture.

• Benign vs malignant visuals (conceptual): benign tumors remain localized with clear borders; malignant tumors appear poorly differentiated, invade, and spread.

• Growth patterns:

  • Benign: grows slowly, remains in local confines, may press on nearby structures.

  • Malignant: rapid growth, invasive, can disrupt normal tissue; may recruit blood supply (angiogenesis) to support growth; may outgrow blood supply leading to necrosis and pain.

• Tumor origin and classification: carcinomas (epithelial tissues), sarcomas (connective tissues like fat, bone, cartilage, muscle), leukemias (blood cell cancers, not solid tumors).

  • Carcinomas comprise ~85 ext{ to }90 ext{ extasciitilde}
    ightarrow ext{percent} of tumors; examples include skin, colon, stomach, breast, lung, prostate cancers.

  • Sarcomas arise from connective tissues and tend to metastasize more rapidly.

  • Leukemias proliferate in the bone marrow and circulate in the blood; they crowd out normal hematopoietic cells and predispose to infection and organ failure.

Cancer Hallmarks and Genetic Factors

• Cancer development is typically multi-step, not caused by a single mutation.

• Key genetic alterations:

  • Activation of oncogenes (mutated proto-oncogenes) that promote cell growth and division (tumorigenesis).

  • Loss of function in tumor suppressor genes (e.g., genes that normally restrain cell division); two alleles often need to be inactivated (two-hit hypothesis).

  • Mutations in DNA repair genes reduce genome integrity, increasing mutation rate and promoting cancer progression.

• Example discussed: APC gene (APC I1307K) mutation in colon tissue; loss of APC gene along with other mutations increases colon cancer risk; individuals with this mutation have higher cancer risk.

• Tumor suppressor genes exist in pairs; both copies must fail for a malfunction to occur.

• DNA repair genes: when mutated, DNA damage accumulates, elevating cancer risk.

• Heterogeneity: tumors contain diverse cell populations with different genetic makeups and behaviors, complicating treatment.

• Angiogenesis: tumors induce new blood vessel growth to supply nutrients and oxygen; vital for tumor growth and potential for metastasis.

• Necrosis: tumors can outgrow their blood supply, leading to necrosis in poorly perfused regions; causes pain and inflammation.

Etiology and Risk Factors

• Etiologic factors contributing to cancer development include:

  • Chemical carcinogens: tobacco smoke, asbestos, benzene, industrial chemicals; cause DNA mutations.

  • Viral oncogenesis: viruses integrate into host DNA and promote tumor formation (e.g., HPV; HTLV-1; HBV; HCV).

  • Genetic predisposition: inherited mutations (e.g., BRCA1/BRCA2 increase risk for breast and other cancers).

  • Lifestyle and environmental factors combine with genetic susceptibility.

• Viruses and cancers:

  • HPV: cervical cancer risk with long-term infection if not monitored by screening.

  • HBV/HCV: increased risk of liver cancer.

  • HTLV-1: associated with certain leukemias/lymphomas in immunocompromised individuals.

Oncoproteins, Tumor Suppressors, and Checkpoints

• Oncogenes vs proto-oncogenes: proto-oncogenes normal growth-promoting genes; mutations convert them to oncogenes that drive uncontrolled growth.

• Tumor suppressor genes: normally restrain growth; loss of function promotes malignancy; often require both alleles to be inactivated.

• DNA repair genes: maintain genome integrity; mutations increase genome instability and cancer risk.

• Oncofetal antigens: antigens expressed during fetal development but usually absent in adults; cancer cells may express them; immune checkpoint inhibitors target pathways that limit immune recognition of cancer cells.

• Immunotherapy: strategies to enhance immune recognition of cancer cells (e.g., checkpoint inhibitors) or to target oncofetal antigens.

Viral and Genetic Contributions to Oncogenesis

• Viruses can contribute to cancer by integrating into host DNA and altering cellular signaling.

• HPV is a well-known cervical cancer risk factor; persistent infection and integration can drive malignant transformation if dysplasia progresses.

• HTLV-1 associated with T-cell leukemias/lymphomas in immunocompromised individuals.

• HBV/HCV can lead to hepatocellular carcinoma after chronic infection.

Diagnosis, Screening, and Tumor Markers

• Early detection is critical for better outcomes; various diagnostic approaches include:

  • Medical history and physical examination.

  • Endoscopic and imaging techniques: colonoscopy, endoscopy, X-ray, CT, PET scans.

  • Cytology and pathology: Pap smears, cytology from biopsies or needle aspirates; frozen sections for rapid intraoperative decisions.

  • Tumor-associated antigens (blood tests) to aid detection and monitoring:

  • CEA (carcinoembryonic antigen): elevated in GI tract, pancreas, breast cancers.

  • AFP (alpha-fetoprotein): elevated in primary liver carcinomas.

  • HCG (human chorionic gonadotropin): elevated in some testicular cancers.

  • PSA (prostate-specific antigen): elevated in prostate cancer.

  • Acid phosphatase (historical marker for prostate cancer).

  • Pap tests for cervical cancer; cytology from tumors; biopsy and histology for definitive diagnosis.

• Dysplasia and precancerous conditions:

  • Dysplasia is precancerous and may progress to cancer if untreated.

  • Examples: actinic keratosis (sun-exposed skin—can transform to skin cancer), lentigo maligna (sun exposure—melanoma risk), leukoplakia (white patches in oral mucosa—risk for squamous cell carcinoma).

  • Treatments may include local excision or other therapies (e.g., mouth rinses for leukoplakia) depending on location and progression.

• Staging of cancer:

  • Stage 0: in situ (confined to site of origin, easiest to treat).

  • Stage I–III: increasing spread within local tissues or regional lymph nodes; prognosis worsens with stage.

  • Stage IV: metastasis to distant organs; prognosis is poorer and treatment is more challenging.

  • Staging criteria vary by cancer type; multiple dimensions include local invasion, nodal involvement, and distant metastasis.

• Staging versus treatment decisions: exam notes indicate treatment specifics are outside the course scope; emphasis on understanding staging conceptual framework and screening importance.

Cancer Progression: Summary Points

• Carcinogenesis is multi-step and involves multiple genetic and environmental factors.

• Tumor microenvironment and immune surveillance influence progression and response to therapy.

• Antigen targets and immune interactions influence responses to cancer and the effectiveness of emerging immunotherapies (e.g., checkpoint inhibitors).

Practical Takeaways and Connections

• Immunity concepts connect across lectures: barriers, inflammation, APCs, MHC, T/B cell activation, memory, and checkpoints.

• Hypersensitivity, autoimmunity, and tolerance illustrate how protective immunity can become pathogenic when regulation fails.

• Cancer biology integrates genetics (oncogenes, tumor suppressors, DNA repair), virology (viral oncogenesis), and immunology (immune surveillance, immunotherapy).

• Screening and early detection (dysplasia, Pap smears, colonoscopy, tumor markers) are essential for improving outcomes, even though treatment details are beyond the scope of this course.

Quick Reference: Key Terms and Concepts

• Innate immunity: first line of defense; non-specific; barriers, cells (neutrophils, macrophages), NK cells, complement, fever, inflammation.

• Adaptive immunity: specific, memory; B cells (humoral) and T cells (cell-mediated); APCs, MHC I/II, TCRs.

• Antigen-presenting cell (APC): dendritic cells, macrophages, B cells; present antigens via MHC to T cells.

• Major histocompatibility complex (MHC): I (CD8+, intracellular antigens) and II (CD4+, extracellular/endocytosed antigens).

• Antibodies (immunoglobulins): IgG, IgM, IgA, IgE, IgD; structures (heavy/light chains); isotypes with distinct roles.

• Hypersensitivity types I–IV: IgE-mediated allergies, cytotoxic, immune complex–mediated, delayed-type hypersensitivity.

• Oncogenes vs proto-oncogenes; tumor suppressor genes; DNA repair genes; multi-step carcinogenesis.

• Angiogenesis: tumor blood vessel formation; essential for tumor growth and progression.

• Dysplasia: precancerous changes; potential progression to cancer.

• Tumor markers: CEA, AFP, hCG, PSA, acid phosphatase; used in diagnosis and monitoring.

• Immunotherapy: checkpoint inhibitors; re-engaging the immune system against cancer cells.

• Vaccines: priming adaptive immunity; mRNA vaccines as a modern approach; public health considerations.

• Stage 0–IV: cancer progression from in situ to metastasis; prognosis generally worsens with advancing stage.

Next Topics to Expect

• Pathogens, parasites, and communicable diseases (as announced for the next class).