Exam 3 - M9.4 - 9.6

Human Defense Mechanisms: Overview

• Human defense relies on innate and adaptive immunity to guard against damage and infection.
• Innate immunity offers a rapid, non-specific response as the first and second line of defense. Includes physical, mechanical, and biochemical barriers plus inflammation.
• Adaptive immunity is the third line of defense, triggered by the innate system, and characterized by specificity and memory. It's slower to develop but provides lasting immunity.

First Line of Defense: Natural Barriers

• Natural barriers prevent pathogen entry.
• Physical barriers: Epithelial cells form tight junctions in skin, gastrointestinal, genitourinary, and respiratory tracts. Mucus traps microorganisms and cilia remove them. Skin acidity inhibits microbial growth.
• Biochemical barriers: Secreted substances such as mucus, perspiration, saliva, tears, and earwax trap/kill pathogens. Sebaceous glands make antibacterial/antifungal fatty acids and lactic acid causing acidity. Perspiration, tears, and saliva have lysozyme. Epithelial cells secrete antimicrobial peptides, defending against bacteria, fungi, and viruses. The lungs produce collectins that enhance pathogen recognition.
• Normal Microbiome: Non-disease-causing microorganisms on body surfaces help digestion, produce vitamins, help ion absorption, compete with pathogens, and secrete toxic proteins. Disruption by antibiotics can cause opportunistic infections. The gut microbiome trains adaptive immunity.

Second Line of Defense: Inflammation

• Inflammation is a programmed response to tissue damage, whether septic or sterile.
• It limits damage, destroys contaminants, starts adaptive immunity, and promotes healing.
• Inflammation happens in vascularized tissues, is activated quickly, depends on cellular and chemical components, and is nonspecific.
• Vascular Response: Injury triggers vasodilation and increased permeability, resulting in redness, heat, swelling, and pain and perhaps loss of function. Mast cell degranulation, plasma systems, and cellular products cause these changes.

Plasma Protein Systems (Inflammation)

• Three systems work together to fight inflammation:
• Complement System: Plasma proteins that destroy pathogens and activate both innate and adaptive immunity. It's activated by the classical pathway (antibodies + antigens), the lectin pathway (mannose-binding lectin), or the alternative pathway (bacterial/fungal cell walls). Activation causes anaphylatoxin activity, leukocyte chemotaxis, opsonization, and cell lysis via the membrane attack complex (MAC).
• Clotting System: Plasma proteins activate to form a fibrin clot at the injury. Prevents infection spread, traps microorganisms, stops bleeding, and provides a repair framework. It is Activated by the tissue factor (extrinsic) or intrinsic (contact) pathways, both leading to fibrin formation.
• Kinin System: Enhances inflammation via bradykinin. Bradykinin causes vasodilation, pain, smooth muscle contraction, increased permeability, and may increase leukocyte chemotaxis.
• Tight control mechanisms exist with regulatory enzymes and cascade inhibitors for efficient activation and limited widespread effects.

Cellular Mediators of Inflammation

• Mast Cells and Basophils: Mast cells activate inflammation by releasing histamine, chemotactic factors (NCF, ECF-A), and cytokines (TNF-α, IL-4). Histamine causes temporary smooth muscle constriction and vasodilation, increasing blood flow and permeability. Basophils have similar functions and release IL-4.
• Endothelium: Endothelial cells regulate blood flow and interact with inflammatory mediators. Damage triggers clotting. Pro-inflammatory mediators cause leukocyte adherence and plasma efflux. Endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2), which maintain blood flow and inhibit platelet activation.
• Platelets: Platelets are Involved in clotting, release serotonin, synthesize thromboxane A2, and relocate phosphatidylserine for coagulation.
• Phagocytes (Neutrophils, Eosinophils, Monocytes/Macrophages): Neutrophils are early responders that phagocytose bacteria/debris. Eosinophils target parasites and regulate mast cell mediators. Monocytes become macrophages, which are active phagocytes involved in adaptive immunity and repair.
• Dendritic Cells: These cells Phagocytose molecules and migrate to lymphoid tissue, linking innate and adaptive immunity.
• Natural Killer (NK) Cells and Lymphocytes: NK cells eliminate infected/abnormal cells. Lymphocytes participate in both innate and adaptive immunity.

Cellular Receptors (Inflammation)

• Cells have surface receptors that bind to ligands for activation.
• Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) on microbes and damage-associated molecular patterns (DAMPs) from stressed cells.
• Toll-like receptors (TLRs) recognize microbial components and host factors. Complement receptors (CRs) recognize complement fragments. Scavenger receptors facilitate phagocytosis. Cytoplasmic NOD-like receptors (NLRs) form inflammasomes for inflammatory cytokine activation.

Cellular Products (Inflammation)

• Cytokines regulate innate and adaptive immunity, and can be pro- or anti-inflammatory.
• Chemokines attract leukocytes.
• Interleukins affect cell adhesion, chemotaxis, leukocyte proliferation/maturation.
• Tumor necrosis factor-alpha (TNF-α) induces pro-inflammatory effects, fever, and increased serum proteins.
• Interferons (IFNs) protect against viruses and modulate inflammation, with Type I IFNs inducing antiviral proteins and Type II IFN activating macrophages.

Manifestations of Inflammation

• Local Manifestations: Vasodilation and permeability cause redness, heat, swelling, and pain.
• Exudate varies in composition: serous (watery), fibrinous (thick and clotted), purulent (pus with leukocytes), or hemorrhagic (with erythrocytes).
• Systemic Manifestations: Fever is an early response induced by pyrogens. Leukocytosis is increased leukocytes. Plasma protein synthesis is elevated (acute-phase reactants). Other symptoms include somnolence, malaise, anorexia, and muscle aching.
• Chronic Inflammation: Lasts two weeks or longer and is characterized by lymphocyte/macrophage infiltration, neutrophil activity, and fibroblast activation. Granulomas may form to isolate infections.

Wound Healing

• Wound healing fills, seals, and shrinks wounds, ideally with tissue regeneration. If not, repair results in scar tissue.
• Phases of Wound Healing:
  • Inflammation: Coagulation and infiltration by platelets, neutrophils, and macrophages happens.
  • Proliferation/Reconstruction: Wound sealing and tissue replacement occurs with fibroblast proliferation, angiogenesis, epithelialization, contraction, and matrix remodeling. Granulation tissue grows.
  • Remodeling/Maturation: Continued differentiation, scar formation, and collagen matrix remodeling happens for increased strength.
• Healing by Primary and Secondary Intention: Primary intention (minimal tissue loss, closed edges). Secondary intention (significant tissue loss, extensive replacement).
• Dysfunctional Wound Healing: Impaired healing from ischemia, bleeding, disorders (diabetes, obesity), infection, nutrients, drugs, and tobacco smoke.
• Wound Disruption: Dehiscence (wound pulling apart). Excessive collagen can lead to hypertrophic scars or keloids.
• Impaired Epithelialization/Contraction: Hypoxemia and zinc deficiency impair migration. Excessive contraction can lead to deformities.

Innate Immunity in Newborns

• Neonates have depressed inflammatory/immune function due to transitioning from a sterile environment. There may be impaired neutrophil function, complement deficiency and low MBL levels.

Adaptive Immunity Characteristics

• Adaptive immunity is inducible (produced upon infection), specific (to the infectious agent), long-lived, and has memory (rapid response upon reinfection). It also develops more slowly than inflammation.
• Innate and adaptive immunity are highly interactive.

Humoral and Cell-Mediated Immunity

• Humoral immunity is mediated by antibodies, which defend against extracellular microbes and toxins.
• Cell-mediated immunity is mediated by T cells.

Active vs. Passive Immunity

• Active immunity is long-lived and develops after exposure to an antigen.
• Passive immunity is temporary and results from receiving preformed antibodies or T cells.

Antigens and Immunogens

• An antigen is a molecule that can react with antibodies or lymphocyte receptors.
• An immunogen is an antigen that elicits an immune response.
• Immunogenicity depends on being foreign, size (>10,000 daltons), chemical complexity, and quantity.
• Self-antigens do not elicit responses due to tolerance (central and peripheral).
• An epitope is the specific part of an antigen that is recognized.
• Haptens are small molecules that become immunogenic when bound to larger molecules.
• Allergens induce allergic responses.

Molecules That Recognize Antigen

• Antibodies (Immunoglobulins): Serum glycoproteins produced by plasma cells. IgG (most abundant, placental transfer, long-term immunity), IgM (first produced, agglutination, complement fixation), IgA (secretions, mucosal protection), IgD (BCR), IgE (allergies, parasites). Antibodies have two heavy and two light chains with constant and variable regions. Fab is for antigen-binding and Fc for biologic functions. Complementary-determining regions (CDRs) form the antigen-binding site.
• B-Cell Receptor (BCR) Complex: Membrane-bound antibody (IgM or IgD) on B cells.
• T-Cell Receptor (TCR): Heterodimeric protein on T cells that recognizes processed antigen presented by MHC molecules.

Molecules That Present Antigen

• Major Histocompatibility Complex (MHC): Glycoproteins on cell surfaces (HLAs in humans).
  • MHC Class I: On all nucleated cells and present endogenous antigens; interact with CD8 on cytotoxic T cells.
  • MHC Class II: On Antigen-Presenting Cells (APCs) and present exogenous antigens; interact with CD4 on helper T cells.
• CD1: Primarily on APCs and presents lipid antigens; interacts with NK-T cells.

Antigen Processing and Presentation

• APCs process antigens and present them on MHC molecules to lymphocytes.
• Exogenous antigens are phagocytosed and presented by MHC class II.
• Endogenous antigens are degraded by proteasomes, bind to MHC class I, and are presented.
• CD1 molecules present lipid antigens.

Immune Cell Interactions

• Adhesion molecules facilitate interactions between lymphocytes and APCs.
• Cytokines mediate intercellular communication.

Generation of Clonal Diversity

• Occurs in primary lymphoid organs (thymus for T cells, bone marrow for B cells).
• Somatic recombination of gene segments creates diversity.
• Central tolerance eliminates autoreactive B and T cells.
• Naïve B and T cells migrate to secondary lymphoid organs.

Clonal Selection

• Initiated by exposure to foreign antigen in secondary lymphoid organs.
• Antigen binds to specific BCRs or is presented to T cells with complementary TCRs, leading to proliferation and differentiation into effector/memory cells.
• T-helper (Th) cells differentiate into Th1, Th2, Th17, and Treg subsets. B-cells differentiate into plasma and memory cells via Th2 interaction.

Humoral Immune Response

• Primary response: Slower antibody production, with IgM appearing first, then IgG.
• Secondary response: Rapid, greater IgG production due to memory B cells.

Cellular Immune Response

• Effector T cells and memory T cells protect against pathogens, tumors, and regulate immune responses.
• Superantigens cause polyclonal T-cell activation and cytokine production.

Functions of Antibodies

• Direct effects: Neutralization of pathogens or toxins, agglutination, or precipitation. Indirect effects: Activate complement or opsonization to enhance phagocytosis.
• Secretory Immune Response (Mucosal Immunity): Protects external body surfaces via IgA in secretions.
• IgE Function: Involved in defense against parasites and mediates allergic responses.
• T-Lymphocyte Function:
  • T-Cytotoxic Lymphocytes (Tc cells): Kill infected/cancerous cells presenting antigen by MHC class I.
  • Natural Killer (NK) Cells: Kill abnormal cells lacking MHC class I; involved in antibody-dependent cell-mediated cytotoxicity (ADCC).
  • T Cells That Activate Macrophages (Th1): Secrete IFN-γ to activate M1 macrophages; Th2 activate M2 macrophages; Th17 recruit phagocytes.
  • T-Regulatory Lymphocytes (Treg cells): Suppress the immune response and maintain tolerance.
• Maternal Immunity: Maternal IgG is transported across the placenta to protect the fetus.

Adaptive Immunity Development

• Lymphoid stem cells originate in the bone marrow and migrate to the thymus (T cells) or bone marrow (B cells).
• This process results in immunocompetent T-cells and B cells.
• These immunocompetent lymphocytes migrate to secondary lymphoid organs (spleen and lymph nodes).
• Generation of clonal diversity occurs in the central lymphoid organs (thymus and bone marrow), primarily in the fetus, which produces a vast population of T and B cells capable of recognizing almost any foreign antigen.

Clonal Selection and Immune Response

• Clonal selection is initiated by exposure to foreign antigens and takes place in the secondary lymphoid organs (spleen and lymph nodes).
• When an immunocompetent B-cell encounters an antigen for the first time, only those B cells with a specific B-cell receptor complementary to that antigen are stimulated to proliferate.
• This proliferation results in copies of that particular B-cell, leading to clonal expansion.
• Clonal selection also leads to a second stage of cellular proliferation and differentiation of both B and T cells, enabling a more rapid response upon subsequent encounters with the same antigen. A secondary challenge by the same antigen results in a very rapid production of a larger amount of antibody, which is due to memory cells that require little further differentiation into plasma cells.

Types of Adaptive Immunity

• Two types: Active immunity (produced after exposure to antigen or immunization) and passive immunity (does not involve the immune response, e.g., maternal antibodies).
• Antigens and Immunogenicity: Antigens can react with B and T cells; most are immunogenic, but certain criteria influence immunogenicity (size, complexity, quantity, foreignness).

Antibodies (Immunoglobulins)

• Five classes of immunoglobulins: IgG (most abundant, protects against infection, primary cause of allergies), IgA (secretory immune system), IgM (first exposure), IgE (allergic responses), and IgD.

Adaptive Immunity

• Antibodies circulate in the blood/secretions and defend against extracellular microbes (humoral immunity).
• Effector T cells defend against intracellular pathogens and cancer cells (cellular immunity).

Antibodies Functions

• Functions include neutralizing/blocking the binding of an antigen to a receptor (neutralization), clumping insoluble particles (agglutination), and making something soluble into an insoluble precipitate (precipitation). Indirectly, antibodies can activate the complement system and phagocytes.
• Body lymphoid tissues: Central organs (thymus and bone marrow) and peripheral/secondary organs (spleen and lymph nodes). A secondary challenge by the same antigen leads to a very rapid production of a larger amount of antibody due to memory cells.
• The amount of antibody in circulation is typically referred to as a titer.

Leukocyte Disorders: Quantitative and Qualitative

• Quantitative disorders involve the number of leukocytes (too many or too few), while qualitative disorders involve a disruption of function.
• Leukocytosis: Higher-than-normal leukocyte count from stressors.
• Neutrophilia: Increase in neutrophils.
• Shift to the left: Marrow releases immature neutrophils due to high demand.
• Eosinophilia: Increase in eosinophils associated with allergies and parasitic infections.
• Monocytosis: Increase in monocytes, common with bacterial infection.
• Lymphocytosis: Increase in lymphocytes, usually with viral infections.

Infectious Mononucleosis (IM)

• Benign, acute infection of B lymphocytes by EBV (herpes virus).
• Transmission is via saliva.

Leukemia: Overview

• Disorder of leukocytes in the bone marrow resulting in uncontrolled proliferation of malignant leukocytes and decreased production and function of normal hematopoietic cells.
• Acute leukemia: Undifferentiated/immature cells, abrupt onset.
• Chronic leukemia: More differentiated cells, slow progression.
• AML: Acute myelogenous leukemia; aggressive, fast-growing leukemia with an excessive number of myeloblasts found in the bone marrow and blood.
• ALL: Acute lymphocytic leukemia; aggressive, fast-growing leukemia with too many lymphoblasts.
• CML: Chronic myelogenous leukemia; a slow-growing cancer with too many immature lymphocytes found mostly in the bone and bone marrow.
• CLL: Chronic lymphocytic leukemia; a slow-growing cancer with too many immature lymphocytes found mostly in the bone and bone marrow.
• There is a statistically significant tendency for leukemia to reappear in families, and there is an increased risk in adults with exposure to cigarette smoke, benzene, and ionizing radiation.

Lymphoma

• Lymphadenopathy: Increase in size and number of germinal centers of the lymph node.
• Localized lymphadenopathy: Drainage of an area with inflammation/infection.
• Generalized lymphadenopathy: Result of malignant or non-malignant disease.
• Lymphomas: Proliferation of malignant lymphocytes in the lymphoid system.
• Hodgkin lymphoma derived from a B cell that has not undergone successful immune immunoglobulin gene rearrangement and would normally undergo apoptosis.
• Non-Hodgkin's lymphoma described as a progressive clonal expansion of B-cells, T cells, and natural killer cells. These lymphomas most likely originate from mutations in cellular genes, which may have been environmentally induced.
• Clinical manifestations of Hodgkin lymphoma include fever, weight loss, night sweats, pruritus, fatigue, and large, painless neck.
• Burkitt lymphoma: Highly aggressive B-cell non-Hodgkin lymphoma associated with EBV. Suppression of immune system increases susceptibility.
• Lymphoblastic lymphoma: Rare variant of non-Hodgkin lymphoma, mostly in children/adolescents.

Multiple Myeloma: Overview

• Biologically complex disease with genetic alterations and poor prognosis.
• Splenic Function: Splenomegaly seen in 7-15% of individuals.
• Overactive spleen: Causes hematologic alterations affecting all blood components. Sequesters up to 50% of red blood cells, potentially creating anemia.

Leukocyte Alterations

• Leukocytosis: High leukocyte count due to stress, malignancy, or microorganism invasion.
• Leukopenia: Low leukocyte count due to physiological stressors and pathological conditions.
• Granulocytosis: Increase in neutrophils.
• Shift to the left: Immature cells released from bone marrow.
• Eosinophilia: From parasitic invasion.
• Basophilia: From hypersensitivity reactions.
• Monocytosis: During recuperative phase of infection.
• Granulocytopenia: Significant decrease in neutrophils, often caused by chemotherapy, severe infection, and radiation, and is most often life threatening.
• Lymphocytopenia: Decreased lymphocytes in acute infections and immunodeficiency.
• Lymphocytosis: Increased lymphocytes in viral infections, leukemia, lymphomas, and some chronic infections.

Lymphoid Neoplasms: Leukemias Types

• ALL (acute Lymphocytic Leukemia): A type of leukemia neoplasm that stems from the the precursor B cell.
• CLL (chronic lymphocytic leukemia): A type of leukemia where the peripheral B-cell neoplasm is the immature B-cell.
• AML (acute myelogenous leukemia) and CML (chronic myelogenous leukemia).
• May genetic related and or linked to carcinogenic chemicals like benzene and ionizing radiation.
• ALL is the most prevalent in adults.
• The AML strain affects genes that deal with encoding transcribing factors and affects what genes are turned on for the epigenome.
• Manifestations that that exist when there is a sign of leukemia are fatigue that stems from anemia, bleeding that stems from not enough thrombocytes (platelet), fever from infection or lowered immune system, and weight loss.
• Chemo and other prescription drugs are the primary defense and treatment against leukemia and leukemia stem cells.
• Leukemias include peripheral with B stem cells and B cells and precursor T.

Alterations of Lymphoid Function

• Tumors of primary secondary lymphoid tissues result in an enlarged or inflamed spleen in tissue.
• The major lymphomas are Hodgkin lymphoma HL and non-Hodgkin lymphoma NHL.

Hodgkin Lymphoma

• Characterized by RS or Reed Sternburg cells which are associated wit the infection or cells from a maligned B cell.
• Virus might be involved with HL and genetic might play a role but symptoms are seen with enlarged or swollen mass on the exterior.
• Radiation and chemotherapies can mitigate its affects.

Non-Hodgkin Lymphoma

• The cause if cancerous and enlarged lymph nodes are unmeasurable and linked with economic statuses and poor condition.
• Caused from genetics and viral infections and immunosuppression's in patient who have received organ transplants.
• HL and NHL can survive for long periods by mitigation.
• Burkitt and lymphoma can evolve with patients with immune responses.

Plasma Cell Malignancies

• Affects from the growth of neoplasms b cells and immature plasma cells in tissue through the skeletal system.
• Patients that have MM or multiple myeloma tend to have excess M protein (that act as an abnormal antibody) bence Jones which has chemicals from urine.
• Factors include radiation exposure and chemicals.
• Manifestations from HL include suppressed immune response or reoccurring infection and kidney or renal failure.
• Treatment in chemo.
• In rare cases WM or Waldenstrom Macroglobulinemia result.

Splenic Function Alterations

• Over active reactions or Splenomegaly where the spleen is inflamed may still be normal and is common.
• Inflammation can be linked to congestion or acute infection processes.
• Hypersplenism or an over secretion of the spleen where bad red blood cells occur because of the overzealous nature of the blood that is destroyed and destroyed (anemia results).