Immunology 101 2 Leonard H Sigal MD lensigalgmail

Immunology 101. 2 Leonard H Sigal, MD lensigal@gmail. com

Introduction to Immunology. 2 01 02 03 04 INNATE IMMUNITY VS ADAPTIVE IMMUNITY MEMORY: THE KEY TO AN EFFECTIVE IMMUNE RESPONSE ANTIBODIES: THE HUMORAL IMMUNE RESPONSE TO DISEASE AND VACCINES DISEASES CAUSED BY ANTIBODIES OR THEIR ABSENCE

Terms Innate Immune system- ancient defenses- pre-vertebrates Not response to a specific Ag – pattern recognition; no acquisition of memory; no enhancement of antigen recognition after multiple exposures; nonetheless, VITAL for survival For first 3 to 7 days after onset of infection, this is what keeps you alive Acquired (Adaptive) Immune response-vertebrates (600 mya) Ag-specific receptors-genetic shuffling Anamnestic (memory) responses, increasing specificity and rapidity with repeated exposures to antigen Often uses innate system(s) to enhance efficiency

A REVOLUTION!!! About 600 mya Genetic juggling occurs in a jawless fish RAG- recombination activating genes, which allowed re-ordering of DNA Production of first Ag-specific molecules; the advent of T cells and B cells Prior to this, invertebrates had NO ADAPTIVE RESPONSE, relying solely on (quite effective) innate systems

Acquired (Adaptive) immune response If infection evades first- and second-line defenses (innate immune systems) acquired immune response Memory acquired in prior encounters faster and more efficient subsequent (anamnestic/2 ndary) responses Third-line defense: Humoral and Cellular immunity B cells Memory cells Antibodies T cells Helper T cells Cytotoxic T cells Regulatory T cells Cytokines

Immunoglobulin Terminology Antibody – same as Immunoglobulin Gammaglobulin – the major serum proteins Antibodies/Immunoglobulins within γ globulin fraction Using electrophoresis divided into 6 “fractions”: Albumin α 1 globulin α 2 globulin β globulin γ globulin Pre-α globulin

Immunoglobulin (Ab) Terminology Antibody (Ab): Immunoglobulin (Ig) made by immune response to an Ag Five different types: Ig. G, Ig. A, Ig. M, Ig. D and Ig. E Ig is a lobster-shaped molecule: tail is “Fc” component, arms are “Fab” components Fc (Fragment of rabbit Ig. G that “crystallizes) plugs into receptors on some cells Fc component is unchanging (“Constant”) – all Ig. G Fc components are essentially the same Fab (Fragment “antigen-binding”) does just that – binds to the antigen The part of the Fab recognizing Ag is variable and unique – varies with different Ag targets

Space-filling model of immunoglobulin molecule Fab components Fc component

Immunoglobulin Structure Consists of 2 heavy (H) & 2 light (L) chains Variable (V) regions of H and L chains bind Ag. Two Ag-binding (Fab) sites /molecule V regions from DNA manipulation/ splicing Constant region (Fc) of H chain mediates effector functions contains structures that define: Ig. M, Ig. G, Ig. A, Ig. D, Ig. E

Immunoglobulin molecule is a composite from multiple sites- dependent on RAG DNA editing: Keep one V segment, one D segment, one J segment and delete the rest of the Vs and Ds and Js, while joining the chosen segments V to the D to the J. Now: V-D-J links to the C (“constant”) segment and you have the Ig molecule V (variable) D (diversity) J (joining)

Antibody Functions Neutralize Toxins & Viruses Antibody-dependent cell-mediated cytotoxicity Opsonize Pathogens Activate Complement inflammation

Memory Subsequent exposure to the same Ag gives responses that are: Faster Better Larger More persistent “Fit” is not perfect (“degeneracy”) so there is “cross-fit” of Ab, e. g. , Ab to one adenovirus could bind (and neutralize) other adenoviruses

Humoral Response Primary response: Mainly Ig. M, low affinity antibodies, long lag time. Secondary response: compared with primary response: Much more Ig. G Better binding Higher affinity Shorter lag time Higher titers Longer duration

Production of antibodies Bone marrow produces “B cells” B cells have Ag-specific Ig on their surface, acting as an Ag receptor Encountering Ag, they activate “with some help from their friends” Can become Ab-producing cells (“plasma cells”) or memory cells Memory cells await second exposure

Response to Infection May lead to lifelong humoral immunity, e. g. , measles, mumps Immunity may persist at low level If inadequate memory cell production, the secondary response will be poor If memory cells produced, levels of antibodies will rise quickly after secondary exposure If memory is not induced at all during primary exposure, no immunity

Vaccine efficacy Some give durable and robust response after single inoculation immunity Some must be repeated every few years, e. g. , tetanus Some vaccines require a second shot (“booster”) as part of initiation, e. g. , hepatitis B, zoster/varicella (“Shingrix”) Influenza: New virus, new vaccine needed. Recall “degeneracy”

Acquired immune response is late in the sequence of events For the first 3 to 7 days of sepsis, what keeps you alive is the INNATE SYSTEM

Controls Multiple mechanisms to control production of antibodies Levels (“titers”) go up and then level off or may diminish In some people there is uncontrolled production by a single cell (plasma cell) resulting in many identical daughter cells – a “clone” Monoclonal gammopathy of uncertain significance (MGUS) Multiple myeloma In some people “tolerance” is broken and auto-antibodies are produced

Defective antibody production 1: 350 Caucasians does not make Ig. A is predominant Ig lining the mucosae; Ig. G can take its place Ig. A deficiency is usually asymptomatic Rarely people cannot make Ig at all Can be congenital or acquired Congenital deficiencies can be associated with other “immunodeficiencies” Intravenous or subcutaneous Ig. G

Auto-antibody-mediated diseases Hashimoto thyroiditis Graves disease Addison disease Myasthenia gravis Autoimmune encephalitis Guillain-Barre syndrome Pemphigus and pemphigoid Goodpasture syndrome

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