Immune System: Innate and Adaptive

Immune System Functions

• Defends against pathogens like bacteria and viruses.
• Removes damaged or worn-out cells.
• Identifies and destroys abnormal cells including cancer cells via immune surveillance.
• Leukocytes (WBC) are the primary immune defense.
• Lymphocytes (T & B cells) create the adaptive immune system.

Innate vs Adaptive Immune Systems

• Innate immune system is rapid and nonspecific and doesn't rely on previous immune training or memory.
• Adaptive immune system is slower, specific, and relies on immune training/memory.

Origin of Leukocytes

• Leukocytes originate from hematopoietic stem cells in bone marrow.
• Granulocytes & monocytes are derived from myeloid progenitor cells.
• Lymphocytes are derived from lymphoid progenitor cells.
• Leukocytes reside primarily in circulation (blood & lymph), reside in tissues, or are transitional.
• Granulocytes are made up of Neutrophils, Eosinophils, and Basophils.
• Agranulocytes are made up of Monocytes and Lymphocytes.

Antigen

• Antigen is an antibody-generator and is part of the adaptive immune system.
• It is a substance that triggers an immune response and antibody production.
• Epitope sections of antigens are recognized by the immune system as "non-self."
• Antigens are often proteins or carbohydrates found on the surface of pathogens, pollen, toxins, and transplanted tissues, etc.

Antibody (Immunoglobulin)

• Y-shaped protein produced by B cells in response to antigen.
• Antibodies have a constant region (tail) that determines their class and function.
• The variable region varies to bind specific epitopes.
• Antibodies circulate and bind specific epitopes of specific antigens
• Antibody-tagged antigens are targeted by the immune system for destruction & clearance.

Antigen Presentation

• Cells present their protein contents.
• Cells express Major Histocompatibility Complex (MHC) proteins.
• MHCs are membrane-bound proteins with a binding pocket for specific peptides (protein fragments).
• As proteins are broken down, MHCs bind peptides and present them at the cell surface.
• Most nucleated cells present cytosolic peptides from within the cell.
• Specialized immune cells present peptides they phagocytize to trigger immune responses.

Leukocytes Primary Residences and Functions

• Neutrophils reside in the bloodstream and can rapidly migrate to tissues, primarily functioning in phagocytosis of bacteria and other pathogens also act as first responders to infection
• Eosinophils reside in the bloodstream and within tissues (especially mucosal tissues) and they specifically defend against parasites and allergic reactions.
• Basophils primarily reside in the bloodstream and release histamine and other mediators in allergic reactions and inflammation
• Mast Cells reside in tissues (especially connective and mucosal-like resident basophils) and release histamine and other mediators in allergic reactions and inflammation
• Monocytes reside in the bloodstream and tissues and differentiate into macrophages to perform phagocytosis, antigen presentation, and cytokine production
• Macrophages reside in tissues and perform phagocytosis, antigen presentation, cytokine production, and tissue repair
• Dendritic Cells are in tissues where they perform antigen capture and present them to T cells to initiate adaptive immunity
• T cells reside in the bloodstream and lymphatic system and initiate cell-mediated immunity by directly killing infected cells and immune regulation
• B cells reside in the bloodstream and lymphatic system and are used for humoral immunity as well as the production of antibodies
• Natural Killer (NK) cells reside in the bloodstream and lymphatic system to destroy infected or cancerous cells

Phagocytosis

• Opsonins are molecules that mark a target for phagocytosis and include compliment proteins & antibodies from the adaptive immune system/
• Phagocytes (macrophages and neutrophils) phagocytize pathogens and debris and once engulfed, the phagosome fuses with a lysosome for degradation
• Phagocytes & other leukocytes release cytokines, which are non-antibody proteins that signal the immune system

Lymphoid Tissues

• Lymphoid tissues produce, store, and process lymphocytes.
• Lymphoid tissues include bone marrow, lymph nodes, spleen, thymus, tonsils, adenoids, appendix, and Peyer's patches.
• Lymph tissue intercepts primary sites of invasion, leading to systemic circulation.
• T cells mature and proliferate in the thymus during adolescence.
• Thymus shrinks with age, remote lymphocyte colonies in lymph tissue become increasingly important for proliferation and activation

Inflammation & Innate Immunity

• Rapid and nonspecific response
• Activated by two patterns: Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs)
• PAMPs are exogenous molecules on pathogens not found on host cells
• DAMPs are endogenous molecules indicating damaged "self" cells
• DAMPS & PAMPs are recognized by Pattern Recognition Receptors (PRRs) which are proteins expressed in immune cells that activate an immune response

Inflammation & Innate Immunity: Recruitment

• Inflammation recruits immune cells & proteins to isolate, destroy, and inactivate invaders, remove debris, and prepare for healing & repair.
• Phagocytes & other leukocytes release cytokines, which are non-antibody immune signaling protein compounds.
• Natural killer (NK) cells lyse virus-infected or cancerous cells.
• Complement system includes circulating plasma proteins with cascade chain activation to enhance immune response
• Complement system can cause opsonization, direct lysis, and inflammation.
• Can be triggered by antibodies (classical) or directly by carbohydrates on the pathogen surface where a cascade of activated proteins swarm and lyse the invading cell

Inflammation & Innate Immunity: Steps

1. Bacteria enter broken skin, resident macrophages engulf pathogen, and release cytokines & chemotaxins.
2. Activated mast cells release histamine.
3. Vasodilation & widened capillary pores, while cytokines cause neutrophils & monocytes to stick to endothelia (margination).
4. Diapedesis occurs where neutrophils and monocytes migrate between endothelial cells to the infection site.
5. Monocytes become macrophages, neutrophils and macrophages destroy bacteria.

Adaptive Immune System

• Lymphocyte mediated B & T cells and is trained and specific
• Specific lymphocytes propagate through response to specific pathogens
• There's an established pool of memory cells
• There are two classifications of adaptive immunity: antibody-mediated immunity and cell-mediated immunity

B Lymphocytes (Antibody-mediated immunity)

• Have B cell receptors (BCRs) on the surface that bind specific antigens (epitopes).
• T-dependent antigens (most protein antigens) require binding of helper T cells to activate B cells.
• T-independent antigens (many polysaccharides) do not require helper T cells to activate B cells.
• Activated B cells become plasma cells to mass-produce antibodies and some become memory cells.

B Lymphocytes functions

• Initially produce immunoglobulin M (IgM) which serves as BCR
• When activated to a plasma cell, it primarily forms IgG.
• A subset of activated B cells become memory cells.
• Remain dormant and long-lived.
• Library of B cells allow rapid response if the same antigen is encountered again.

Antibodies (immunoglobulins or γ globulins)

• Grouped into 5 subclasses based on activity and have constant regions that determined the function of the antibody

  • IgM: 5-10% in serum and secreted as pentamer; serves as BCR, first response, complement activation, and agglutination
  • IgG: most abundant in the serum 70-80% and secreted as a monomer; long-term immunity, opsonization, neutralization, complement activation, and crosses the placenta
  • IgA: 10-15% in serum and is secreted as a dimer; mucosal immunity to prevent pathogen entry, in the milk
  • IgE: very low in serum and is secreted as a monomer; allergic reactions with a defense against parasites
  • IgD: very low in serum and is secreted as a monomer; B-cell activation that is not fully understood

Antibodies function

• Hinder antigen/pathogen function or amplify innate immune function
• Neutralize by attaching to a virus or toxin to neutralize it
• Agglutination cross-links antibodies and antigens into clumps
• Activate the complement system of humoral proteins to swarm and lyse a cell
• Enhance phagocytosis via opsonization, particularly through IgG.
• Stimulate NK cells by antibody tails binding and activating NK cells.

T Lymphocytes (Cell-mediated immunity)

• T cell receptors (TCRs) are on the surface and bind specific antigens (epitopes).
• Additional co-receptors recognize specific MHCs.
• Originate in bone marrow but mature in the thymus (T-cell).
• Defend against intracellular threats (cancer or virus)
• Two main types of T cells: cytotoxic T cells (CD8+) and helper T cells (CD4+)
• Regulatory T cells (CD4+CD25+) "Treg" dampen the immune response.

Cytotoxic T Cells

• Class I MHCs (all nucleated cells) present intracellular proteins on the surface.
• CD8+ coreceptor identifies Class I MHCs on the surface of all nucleated cells.
• Activated by binding both the TCR to foreign antigen & CD8+ to Class I MHC.
• The CD8 coreceptor links cells together
• Cytotoxic substances are released to destroy cells that have cancer or cells that are infected with a virus.

Helper T Cells

• Class II MHCs (in antigen-presenting cells) present extracellular-derived (phagocytized) peptides on the surface.
• A CD4+ coreceptor identifies Class II MHCs on the surface of APCs (dendritic cells, macrophages, & B cells).
• Activated by binding both the TCR to foreign antigen & CD4+ to Class II MHC.
• The CD4+ coreceptor links cells together.
• Activated helper T cells release cytokines to proliferate & activate other T cells, activate B cells to produce antibodies, and stimulate macrophages for phagocytosis.

Regulatory T Cells (CD4+CD25+ "Tregs")

• Subclass of helper T cells
• Act as a check on immune system function to create balance
• Suppress immune responses, prevent autoimmunity, & maintain immune homeostasis
• Secrete immunosuppressive & anti-inflammatory cytokines (e.g. IL-10)
• Expresses CD25 (IL-2 receptor) and removes IL-2, which is a growth & activation factor for T cells

Key Features: Innate vs Adaptive Immune System

• Innate immune system response is rapid (minutes to hours), while the adaptive system is slow (days to weeks)
• Innate System specificity is limited and recognizes general PAMPs and DAMPs, while Adaptive is highly specific and recognizes unique antigens
• Innate system has no memory with the same response to repeated exposure, while adaptive Subsequent exposures elicit a faster and stronger response (immunological memory)
• Key components of the innate Immune System includes Physical barriers (skin, mucous membranes), chemical barriers (enzymes, pH), cellular components (neutrophils, macrophages, NK cells, mast cells), complement system, and PRRs (TLRs, NLRs), while the adaptive immune system includes Lymphocytes (T cells, B cells), antibodies, and antigen-presenting cells (APCs)
• Activation Trigger for the innate immune system includes PAMPs and DAMPs while the adaptive system is specific antigens
• Recognition Mechanisms for the innate immune system include Pattern Recognition Receptors (PRRs) recognizing PAMPs and DAMPS, while adaptive immune system includes Antigen receptors (T cell receptors and B cell receptors/antibodies) recognizing specific antigens
• The major function of the innate immune system is the first line of defense, immediate response, inflammation, and activation of adaptive immunity, while the adaptive immune system is the targeted destruction of pathogens, long-term immunity, antibody production, and cell-mediated immunity
• Cellular Players of the innate immune system include Neutrophils, macrophages, dendritic cells, natural killer (NK) cells, mast cells, eosinophils, and basophils, while the adaptive immune system includes T lymphocytes (helper, cytotoxic, regulatory), and B lymphocytes (plasma cells, and memory B cells)
• Humoral components for the innate immune system include the Complement system and antimicrobial peptides, while adaptive immune system includes antibodies (IgG, IgM, IgA, IgE, and IgD)