The Immune Response

• The immune response is essential for survival.

Failures of the Immune Response

• Hypersensitivity occurs when the immune response is excessive.
• Immunodeficiency arises when the immune response is insufficient.
• Autoimmunity happens when the immune system attacks the wrong target.

Weapons of Immune Response

• Lymphocytes, macrophages, and dendritic cells are key components.

Cells of the Immune System

• T lymphocytes are thymus-derived cells mediating cellular immunity, making up 60-70% of peripheral lymphocytes.
• T lymphocytes are genetically programmed to recognize specific antigens via T-cell receptors (TCR).
• Subclasses of T lymphocytes include helper CD4+, cytotoxic CD8+, and gamma/delta T lymphocytes.
• Gamma/delta T lymphocytes colonize epithelia, serving as a first line of defense.
• B lymphocytes are bone marrow-derived precursors of plasma cells, constituting 10-20% of peripheral lymphocytes.
• Each B cell receptor has unique antigen specificity.
• Natural killer cells (NK) account for 10-15% of peripheral lymphocytes and can lyse tumor cells, virus-infected cells, and some normal cells.
• NK cells are programmed to recognize transformed cells, releasing perforins and granzymes.
• Macrophages are derived from monocytes, process and present membrane-bound antigens to T cells and phagocytose opsonized microbes.
• Dendritic cells are marrow-derived, non-phagocytic, present antigens to CD4+ T cells, and are widely distributed.
• Langerhans cells are dendritic cells of the skin, trapping antigens bound to antibodies and migrating to regional lymph nodes.
• Follicular dendritic cells are in germinal centers of the spleen and lymph nodes, intimately contacting B lymphocytes.

Messenger Molecules of the Immune System

• Cytokines mediate natural immunity, regulate lymphocyte growth, activate inflammatory cells, affect leukocyte movements (chemokines), and stimulate hematopoiesis (colony-stimulating factors - CSFs).
• Cytokines that mediate natural immunity include IL-1, IL-6, type 1 interferons, and TNF-a.
• Cytokines that regulate lymphocyte growth, activation, and differentiation include IL-2, IL-4, IL-5, IL-12, IL-15, and TGF-b.
• Cytokines that activate inflammatory cells include INF-g, TNF-a, and TNF-b.
• Cytokines have a wide spectrum of effects and can be produced by several different cell types.
• Cytokines can act on many cell types (pleiotropic) and bind to specific high-affinity receptors on target cells.
• Cytokines can have autocrine, paracrine, or endocrine effects.

Cell Killing Mechanisms

• Natural killer (NK) cells, cytotoxic T and B lymphocytes, and macrophages specialize in cell killing.
• Mechanisms of killing involve inserting plugs (perforins/cytolysin), producing burns (oxygen-derived free radicals), and inflicting toxic damage (apoptosis induction with cytokines).
• Activated macrophages kill via TNF, while activated T lymphocytes kill via lymphotoxin.
• Eosinophils use plugs and burns, lymphocytes use plugs and poisons, and macrophages use burns and poisons.

Disorders of the Immune System

• Hypersensitivity reactions involve unnecessary or exaggerated immune responses where the response poses a greater hazard than the antigen.
• The immune system reacts against a harmless antigen in hypersensitivity reactions.
• Types of hypersensitivity reactions include Type I (anaphylactic), Type II (cytotoxic), Type III (complex-mediated), and Type IV (cell-mediated).
• Types I, II, and III are immediate (seconds to hours) and depend on B cells and antibody production.
• Type IV is delayed (12-18 hours) and depends on T cells, independent of antibody production.

Hypersensitivity Reactions - Type I (Anaphylactic)

• Degranulation of mast cells coated with IgE antibody is induced by exposure to a specific antigen.
• Anaphylactic shock involves general degranulation and can be fatal.
• Allergy represents local degranulation.
• Massive allergic mast cell degranulation is the mechanism.

Diseases Related to Anaphylactic Sensitivity

• Anaphylactic shock is an acute clinical syndrome resulting from generalized degranulation, with a mortality rate of ~10%.
• Anaphylactic shock can be induced by venom, pollen, or drugs like penicillin, which kills 500 people/year.
• Symptoms of anaphylactic shock include itching (palms and soles), skin rashes, nausea, vomiting, cardiovascular collapse, bronchial spasm, and laryngeal edema, varying between species.
• Allergies involve local degranulation.
• Hay fever results from inhalation of pollen, leading to an inflammatory response.
• Food allergies are triggered by antigens crossing the intestinal epithelium barrier.
• Allergic asthma involves mast cell degranulation, leading to bronchospasm.
• Urticaria or hives result from local mast cell degranulation of any kind, not just via the IgE mechanism.
• Anaphylactic responses may be an adaptation leftover from times when infestations with worms were prevalent, responding to environmental antigens by the same IgE-mast cell degranulation mechanism.
• Anaphylactoid reactions involve mast cells degranulating for various reasons unrelated to IgE.
• Anaphylactoid reactions can occur in response to drugs (morphine, opiates, chemotherapeutic agents, polymyxin B, mannitol), cold, curare and other muscle relaxants, intravenous iodinated contrast media, and exercise, and do not occur in all individuals.

Hypersensitivity Reactions - Type II (Cytotoxic)

• Mast cells are not involved in Type II hypersensitivity.
• Antibodies bind to harmless antigenic surfaces, leading to the destruction of specific structures for no good reason by complement or leukocytes.
• Mechanisms include antibody-dependent complement-mediated and antibody-dependent cell-mediated mechanisms.
• Diseases occur when the surface marked for destruction is a normal part of the body. Examples include ABO mismatch, mother-fetus mismatch (RhD incompatibility), normal surfaces becoming antigenic, targeting allografts, and targeting receptors (autoimmunity like myasthenia gravis and Graves’/Hashimoto’s diseases).
• Myasthenia gravis involves antireceptor antibodies binding to acetylcholine receptors, impairing neuromuscular transmission.

Hypersensitivity Reactions - Type III (Complex-Mediated)

• Complexes of antigen and antibody activate complement, attracting more leukocytes.
• Damage to nearby tissue is done mainly by neutrophils.
• Immune complex-mediated injury can be caused by exogenous antigens (virus, bacteria, foreign protein) or endogenous antigens (antibodies produced against self-components).
• Diseases can be generalized (systemic) with complexes formed in circulation and deposited in many organs, or localized with particular organs affected (joints, kidney, small vessels of the skin).

Systemic Immune Complex Diseases

• Serum sickness ("serum fever" or "serum rush") was originally named from the treatment of diphtheria and scarlet fever with antibodies from immunized horse serum.
• It can be produced by drugs that combine with plasma proteins and turn them into antigens.
• Serum sickness can be a result of administration of high doses of foreign serum (for passive immunization e.g. tetanus), antibiotic therapy, or administration of horse antithymocyte globulin (treatment of aplastic anemia).
• Phases include formation of antigen-antibody complexes in circulation, deposition of immune complexes in various tissues, and inflammatory reaction in dispersed sites throughout the body.
• Morphology includes acute necrotizing vasculitis and glomerulonephritis.

Hypersensitivity Reactions - Type IV (Cell-Mediated)

• No antibodies are involved; only cells participate.
• Target antigenic cells are killed by killer cells and lymphokines; it is delayed.
• Initiated by sensitized T lymphocytes.
• Principal pattern of immunologic response to intracellular bacteria (tuberculosis, leprosy), viruses (smallpox, measles, herpes), fungi (candidiasis), protozoa, parasites, graft rejection, and contact skin sensitivity to chemical agents (dermatitis).
• Two forms: delayed-type hypersensitivity and T cell-mediated cytotoxicity.

Delayed-Type Hypersensitivity (DTH)

• Classic example is the tuberculin reaction after intracutaneous injection in previously sensitized individuals.
• This type of hypersensitivity is a major mechanism of defense against a variety of pathogens, but can also cause disease, such as contact dermatitis.
• Poison ivy or poison oak cause tissue injury due to delayed hypersensitivity.

T Cell-Mediated Cytotoxicity

• Sensitized T cells, or cytotoxic T lymphocytes (CTLs), kill antigen-bearing target cells.
• CTLs play an important role in resistance to virus infection by killing virus-infected cells before viral replication is completed.
• CTLs are important in graft rejection and may be involved in tumor immunity.