Immunology Part 2: Secondary Lymphoid Organs

Part 2: Immunology

• Mohamad Razif bin Othman, PRH 1026

Previously in Part 1

• Organisation of the immune system
• Leukocytes
• Types of granulocytes
• Lymphatic system
• Organs of immune system
• Bone marrow
• Thymus

Secondary Lymphoid Organs

• Have two major functions: trapping and concentrating foreign substances, and acting as main sites of antibody production and T cell activation
• Organs include lymph nodes, spleen, and MALT

Lymph Nodes

• Filter lymph, which drains antigens from tissues
• Found at junctions of lymphatic vessels
• Bean-shaped structures

Lymph Node Anatomy

• Cortex (outer layer): Sites of B cell development and maturation into plasma cells with germinal centers
• Paracortex (middle layer): Contains antigen-presenting cells (APCs) like dendritic cells that activate T cells
• Medulla (inner part): Lymph enters from outside surrounding the cortex and filters toward the medulla where it exits

Spleen

• Main function: to filter blood
• Consists of compartments including red and white pulp

Spleen Functions

• White pulp: Associated with immune function and contains primarily T cells
• Red pulp: Associated with removing aged erythrocytes and platelets and contains macrophages
• Marginal zone: Separates the white and red pulp and contains lymphoid follicles with many B cells

Mucosal-Associated Lymphoid Tissue (MALT)

• Lymphoid tissue that lines mucous membranes associated with the gastrointestinal tract, thyroid, breast, lung, salivary glands, eye, and skin
• Blocks entry of microorganisms via these routes
• Forms adenoids, tonsils, appendix, and Peyer's patches in some areas
• More antibody-producing plasma cells are found in MALT than in combined spleen, lymph nodes, and bone marrow
• Major effector mechanism is slgA secreted into the mucosa

Lymphocyte Recirculation

• 70% of cells in the circulating pool undergo a cycle, exiting the systemic circulation to return to lymphoid follicles, lymph nodes, and spleen to start over
• Lymphocytes in systemic circulation represent a mixture of cells from bone marrow and thymus
• Lymphocytes exit via lymphatics and from direct discharge into the vascular system
• Cells in recirculating pool are mostly long-lived mature T cells

Learning Objectives 3

• Describe and list types of innate immunity
• Describe and list types of acquired immunity
• Describe the role of cytokines and the complement system in the immune system
• State the stages of acquired immunity

Host Defenses & Immunity

• Two types of immunity: innate (natural) and acquired (adaptive)
• Innate immunity includes physical defenses, chemical elements, and commensal organisms
• Acquired immunity is adaptive

Innate Immunity: Physical (Superficial) Defenses

• Examples include skin, mucous membranes, and the cough reflex
• Skin acts as a mechanical barrier to microorganisms, aided by the fatty acid content of sweat and sebum
• Microbes can bypass these defenses through wounds, burns, and vitamin deficiency

Innate Immunity: Chemical (Superficial) Defenses

• Chemical defenses include pH, hydrochloric acid, lysozyme, digestive enzymes, and histamines
• Tears containing lysozyme wash the conjunctivae
• Saliva has lysozyme and lactoferrin
• Mucous membrane and mechanical flushing are also defenses

Innate Immunity: Commensal (Superficial) Organisms

• Gut flora prevent the colonization of the body's external and internal surfaces by pathogenic microorganisms.

Innate Immunity: Cellular Defenses

• Innate response is the first line of defense and is active even before infection starts

Key Cellular Defenses

• Cytokines: Soluble factors produced by cells, including interleukins (IL), interferons (IFN), and colony stimulating factor (CSF)
• Phagocytosis: Engulfing of microorganisms by host cells, specifically neutrophils, monocytes, and macrophages
• Cytolysis: Natural killer (NK) cells destroy virus-infected cells through an extracellular killing mechanism

Cytokines

• General term for protein molecules that signal between cells during immune responses
• Includes lymphokines (cytokines produced by T lymphocytes) and monokines (produced by mononuclear phagocytes)

Cytokines: Interferons (IFN)

• Immunoregulatory cytokines produced very early during viral infections
• First line of resistance against many viruses
• IFN-a and IFN-b are produced by virus-infected cells
• IFN-g is released by T lymphocytes and NK cells

Cytokines: Interleukins (IL)

• General term for numerous cytokines synthesized by leukocytes
• Includes multiple secreted proteins that facilitate inflammation exchange among leukocytes and direct the division and differentiation of many cell types
• Most interleukins are made by T cells

Cytokines: Colony Stimulating Factors (CSF)

• Govern the formation, differentiation, and function of hematopoietic cells
• Circulate in the blood, acting as hormones, and are also secreted locally
• Made by monocytes and macrophages

Complement System

• A group of plasma protein mediators acting as an innate nonspecific defense to connect innate and adaptive immunity
• Consists of more than 30 proteins that help eliminate infectious microorganisms causing lysis of foreign and infected cells, the phagocytosis of foreign particles and cell debris and inflammation of surrounding tissue

Complement Activation

• The Classical pathway: triggered directly by a pathogen or indirectly by antibody binding
• The Mannan Binding-Lectin pathway: initiated by binding of the mannan-binding lectin to mannose-containing carbohydrates on bacteria or viruses
• Alternative pathway: initiated when a spontaneously activated complement component binds to the surface of a pathogen

Complement System Role

• Plays a critical role in inflammation and defense against bacterial infections
• Activated during reactions against incompatible blood transfusions, and during the damaging immune responses that accompany autoimmune disease

Acquired (Adaptive) Immunity

• Immunity that develops with exposure to various antigens
• Immune system builds defense specific to that antigen
• Specific response to each infectious agent acquired during the lifetime of the individuals

Stages of Acquired Immunity

• Recognition
• Discrimination
• Implementation

Recognition Stage

• The immune system must recognize the presence of threatening microorganisms to detect and respond

Discrimination Stage

• The immune system must discriminate between microorganisms and normal body cells
• It must differentiate between itself and foreign microorganism
• The system faces two choices: ignore or react

Implementation Stage

• Actions that eliminate the microbial threat via antibody, NK cells etc
• The process is useless if it recognizes the microorganism as foreign but then allows it to persist and cause disease

Learning Objectives 4

• Describe the cells involved in the acquired immune system
• Describe the function of APC cells
• Describe humoral and cell-mediated immunity mechanisms
• Describe the MHC pathways

Immune Responses

• Responses occur in two forms and develop concurrently: Humoral-mediated (B cell) and Cell-mediated (T cell)

Main Cells Involved

• B lymphocytes: Secrete antigen-specific antibodies
• T lymphocytes: Secrete cytokines and are cytotoxic for virally-infected cells, tumors, and foreign tissue grafts

Lymphocytes: B Cells

• Antigen receptors on B cells' surface are membrane-bound antibody molecules
• B cells divide and differentiate into plasma cells when an antigen contacts the B cell's receptors
• Plasma cells secrete large amounts of antibody into blood and tissue fluids
• The antibody then binds to the antigen and neutralizes it
• In mammals, B cells mature in the bone marrow
• Only mature B cells have immunoglobulin molecules bound to their surface
• Each antibody on the surface has the same antigenic specificity

B Lymphocytes: Activation

• When an antigen binds to the antibody on the surface of a B cell (with additional signals from an activated T cell), the B cell multiplies
• Some progeny become plasma cells, producing vast numbers of secreted antibodies rather than membrane-bound antibodies
• Each of these antibodies will have the same antigenic specificity as the original engaged surface molecule

T Lymphocytes

• The "T" in the name comes from the thymus where these cells mature
• T cells have antigen receptors called TCR (for T cell receptors) on their surface
• Unlike antibody molecules (including B cells) that recognize antigen free in solution, the TCR recognizes it in the context of a self-MHC molecule
• This antigen-MHC molecule complex is displayed on the surface of antigen-presenting cells

Lymphocytes: T Cells

• Two main types of T lymphocytes: Cytotoxic T lymphocytes (CTL) and Helper T cells (Th Cells)
• Cytotoxic T lymphocytes (CTL): Destroy tumor cells and host cells infected by intracellular pathogens
• Helper (Th Cells): Produce cytokines that stimulate B cells to make antibody and mononuclear phagocytes to kill pathogens
• Other types of T lymphocytes include Regulatory (Suppressor) (Ts cells) and Memory T cells

Helper T cells (Th Cells)

• Helper T cells (Th cells) express the CD4 molecule
• Will respond to antigen presented in the context of MHC Class II molecules
• They are responsive to antigen presented by antigen-presenting cells (APCs) such as macrophages, B cells, and dendritic cells
• Respond to activation by secreting a variety of cytokines which allow B cells to mature and develop into plasma cells

Cytotoxic T cells (CTL)

• Cytotoxic T cells (CTLs) express the CD8 molecule
• Will respond to antigen presented in the context of MHC Class I molecules
• They can respond to antigens presented by virtually any nucleated cell
• Respond to activation by developing into cytotoxic T lymphocytes that can kill abnormal self-cells (tumor cells) or cells infected with a virus

Regulatory (Suppressor) T Cell (Treg cells)

• A T lymphocyte subpopulation that diminishes or suppresses antibody formation by B cells or downregulates the ability of T lymphocytes to mount cellular immune response
• Significant in the establishment of immunologic tolerance and are particularly active in response to unprocessed antigen
• Some CD8 T lymphocytes diminish T helper CD4 lymphocyte responsiveness to endogenous and exogenous antigens, leading to suppression of immune response