IMMUNE RESPONSE
First Line of Defence: Skin and Mucus Membranes -- Non-Specific A. Skin Surface B. Mucus Second Line of Defence: Non-Specific Internal Defences -- Non-Specific A. Cells 1. Phagocytic Cells a. White Blood Cells b. Macrophages - engulfing behaviour 2. Natural Killer Cells a. recognize body cells infected with foreign bodies (i.e. viruses) b. transfer membrane containing "hole-forming" proteins c. secrete enzymes
Antimicrobial Proteins: Complement System a. group of at least 20 proteins, circulate in blood b. activated in a progressive (cascade) fashion; - "classical pathway": initiated with antibodies (specific targets). - "alternative pathway": init. by microbial substances (non-spec.) b. lyses invading microbes. c. some proteins are chemo attractants for phagocytes (smell). Interferon's a. produced by viral infected cells, help neighbour cells - neighbours produce proteins which inhibit viral replication b. three types: alpha, beta, gamma c. pre-antibody response, early response, short-term infections d. gamma activates phagocytes
Inflammatory Response: Damaged cells release HISTAMINE a. histamine makes capillary walls leaky b. relaxes smooth muscle c. result: blood flows into wounded area: inflammation - increased delivery of WBCs, etc. Clotting response - chemically stimulated by wounded cells (platelets, etc.) Attraction of Phagocytic WBCs (i.e. Macrophage) / pus Fever a. hypothalamus controls body thermostat (set point: 37oC). b invasion > specific WBCs release hormones: "endogenous pyrogens" c. pyrogens travel blood > hypothalamus, inducing thermostat change d. elevated temperature... - inhibits bacteria metabolism - stimulates phagocytic WBCs - increases production of interferon in viral attacks -aspirin reduces fever; prolongs viral (flu) infections
Third Line of Defense: Immune Response – Specific Complex system of interacting cells: WBCs
B-Cells: Humoral Immunity a. born and differentiate in bone marrow
T-cells: Cell-Mediated Immunity a. born in bone marrow, migrate to and differentiate in thymus Macrophages: trigger T-Cell response
Primary response The primary antibody response has four phases:
Inductive, latent, or lag phase –
Antigen is recognized as foreign and the cells begin to proliferate and differentiate in response to the antigen. The duration of this phase will vary depending on the antigen but it is usually 5-7 days. The plasma cells begin to secrete antibody. Log or Exponential Phase –
As more B cells proliferate and differentiate into antibody secreting cells, the antibody concentration increases exponentially. The plasma cells initially secrete IgM antibody. Eventually some B cells switch from making IgM to IgG, IgA or IgE.
Plateau or steady-state phase – As antigen is depleted, T and B cells are no longer activated. In addition, mechanisms which down-regulate the immune response come into play. Furthermore, plasma cells begin to die. When the rate of antibody synthesis equals the rate of antibody decay the stationary phase is reached.
Decline or decay phase –
The rate of antibody degradation exceeds that of antibody synthesis and the level of antibody falls. Eventually the level of antibody may reach base line levels.
Secondary response
The secondary, memory, or anamnestic* antibody response also has four phases:
Inductive, latent, or lag phase – This is normally shorter than that observed in a primary response. Log or Exponential Phase – The log phase in a secondary response is more rapid and higher antibody levels are achieved. Plateau or steady-state phase – No difference. Decline or decay phase – The decline phase is not as rapid and antibody may persist for months, years or even a lifetime.
B lymphocytes and antibody-mediated immunity Antibodies are formed even before an antigen is ever seen. The particular antibody is selected by the antigen. What exists is a collection of B lymphocytes capable of responding to any conceivable antigen. Each lymphocyte is programmed to make one, and only one, antibody. The B cell places this antibody on its outer, where it acts as a receptor. Each lymphocyte has about 105 antibody molecules on its surface.
B-Cell Receptors: Antibodies
Structure: - Y-shape
- four subunits: 2 heavy chains, 2 light chains - constant regions - variable regions Variable regions bind ligands: each cell produces identical antibodies with identical specificities > 1,000,000,000,000 different specificities (more than # of lymphocytes) specificity in the amino acid sequence/conformation of variable ends
Two mechanisms generate diversity (>1012):
only 100,000 total genes in human; only several hundred antibody related genes stem line gene rearrangements - clonal lines of specific types numerous variable regions, constant regions for both heavy and light chains early development: random joining of variable/constant regions somatic mutations variable regions are hypersensitive to induced mutations small changes produce significant differences in specificities Result : many cells / millions of different receptor specificities
Various forms of B-Cell receptors: IgM, IgG, IgA, IgE, IgD: all have basic structure B-cell receptors recognize foreign material: NOT SELF Major Histocompatibility Complex (MHC) family of cell surface proteins unique to each individual must be present from embryogenesis
Attack: B-Cell Response: extracellular invaders:
Foreign antigen binds to antibodies of a specific B-cell Antigenic binding stimulates cell division of activated B-cell 3. Clonal selection: antigen stimulates a line of clones 4. Activated B-Cells differentiate a. Plasma cells: secrete antibodies b. Memory cells: persist in background, primed for future attack 5. Antibodies neutralize foreign body a. cover body b. promote phagocytosis by covering body c. agglutination d. complement reaction
1. 2.
plasma cell differentiation:
Lymphocytes whose receptors have bound antigen are stimulated into developing into antibody-forming plasma cells. Since the B cell that was programmed to make only one type of antibody, the derived plasma cell will also make only that antigen. Clonal selection theory of B cell production Because we can make such a large number of different antibody molecules It is not practical to have too many lymphocytes producing each antibody type. To compensate for the paucity of lymphocytes, those which are triggered by contact with antigen undergo successive waves of proliferation to build up a large clonal set of plasma cells which will be making the antibody for which the triggered lymphocyte was programmed. By this system, large quantities of antibody can be produced for effective elimination of the antigen.
Cell-Mediated Immunity
Cell-mediated immunity results from the formation of activated T cells Participate in attack and destroy the target. Internship and residency of Lymphocytes: lymphocytes released from the bone marrow are immunologically incompetent. This competency must be acquired by residency in either another bone marrow compartment (B cells) or the thymus (T cells). For example: T cells which enter the thymus are CD4-/CD8-, become double positive, CD4+/CD8+ cells expressing low levels of the T cell receptor (TCR).
Positive selection for interaction with self MHC-I or MHCII molecules occurs in the cortical epithelium of the thymus.
The majority of the cells are unselected and undergo apoptosis (self-programmed death). The cells that remain either interact with MHC-I and lose their CD4 antigen (becoming CD8+ T cells) or interact with MHC-II and lose their CD8 antigen (becoming CD4+ T cells). Autoreactive cells are then removed as a result of their i interaction with self antigen peptides that are presented by cells in the corticomedullary junction and the medulla of the thymus.
Attack: T-Cell Response: intracellular invaders
Viral attacked cell ingested by macrophage: a. viral proteins combine with MHC proteins - antigens recognized by specific Virgin T-cell receptors - activates specific Virgin T-cell class Activated Helper T-Cells are Core of Immune Response a. Activated Virgin T-Cell releases Interleukin b. Interleukin stimulated T-Cell divisions: progeny - some become Memory Helper T-Cells - others activate Cytotoxic T-Cells Virgin Cytotoxic T-Cells recognize invading antigen a. Virgins gaining experience are sensitive to Interleukin b. Experienced Virgins divide in response to hormone c. Cytotoxic T-Cell response is amplified, along with B-Cell response Suppresser T-Cells Turn off Immune Response
T cell types: Cytotoxic T cells (CD8+ or TC cells): These cells destroy host cells harboring anything foreign and bearing foreign antigen. E.g: such as body cells invaded by viruses, Cancer cells that have mutated proteins resulting from the malignant transformation, Xenografts (cells transplanted from another host). Besides the perforin method, cytotoxic T cells appear to be able indirectly to bring about the death of infected host cells by producing chemicals that induce them to self-destruct (a process called apoptosis). After the cell is destroyed, the released viral particles can be easily dealt with by other elements of the immune system T cell can merrily move on to its next victim.
Perforin molecules: The direct means used by cytotoxic T cells is the same as used by NK cells Releasing perforin molecules which penetrate into the target cell’s surface membrane and join together to form large pore like channels.
Helper T cells (CD4+ or TH cells) These cells enhance the development of antigenstimulated B cells into antibody-secreting plasma cells Enhance the activity of cytotoxic and suppressor T cells Activate macrophages. Releasing chemicals- now well-known cytokines
T helper 1 (TH1) cells:
TH1 cells are formed from the naïve pool by secretion of IL-12 by the presenting dendritic cell. These TH1 cells secrete IFNγ to activate macrophages, promoting a cell-mediated (cytotoxic T cell) response. Are best suited for responding to intracellular microbial infections. IFNγ produced by TH1 cells inhibits proliferation of TH2 cells cells T helper 2 (TH2) cells:
TH2 cells are formed from the naïve pool by secretion of IL-4 by the presenting dendritic cell. These TH2 cells promote a humoral (B cell) response. Produce IL-4 and IL-5 that increases production of eosinophils and mast cells and enhances production of antibody-IgE. Similar to what happens with TH1 cells, IL-10 produced by TH2 cells cells inhibits production of IFNγ and, IL-4 inhibits the production of TH1 cells.
Suppressor T cells (TS cells): These are the least well-known of T cells. Suppressor T cells do not have to be presented antigen to become active. They seem to limit immune reactions.. They may have a very important role in tolerance, autoimmune disorders, and certain cancers.
Central Role of Helper T-Cells for BOTH B- and T-Cell Response
Physical and hormonal (Interleukin) interactions Helper T-Cells - positive feed back Cytotoxic T-Cells - reinforce antigenic interactions Cells - reinforce antigenic interactions
Inhibition by TS cells:
Both low and high doses of antigen may induce suppressor T cells which can specifically suppress immune responses of both B and T cells. Either directly or by production of cytokines -TGF-β and IL-10.
Antigen sequestration (or clonal ignorance): T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery. They may never encounter the appropriate antigen because it is sequestered in inaccessible tissues. Such cells may die out for lack of stimulus. Auto-reactive B cells that escape deletion may not find the antigen or the specific helper T-cells Hence not be activated and die out.
A few examples of sequestered antigens: Proteins within the lens, shielded by the capsule; Thyroglobulin within the thyroid follicles; Enzymes forming on the acrosomes of developing spermatozoa on the other side of the blood-testis barrier.