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Immunology
- 1. Immunolo gy By Amir Salahuddin Periodontist & Oral Hygienist
- 51. Thank you
Editor's Notes
- Any multicellular organism has immune system. The vertebrates have 2 types of immune systems the innate and the adaptive immune systems.
- the successful side of the immune system through its defensive role against microbial infection and tumor cells. And to recognize the damaged tissue and enhances its repair. The effectiveness of the immune system is due to two main features: (i) the wide range of pathogens it can specifically recognize and remember, and (ii) the effective mechanisms to eliminate them.
- The mechanisms of innate immunity provide the initial defense against infections. Some mechanisms (e.g., epithelial barriers) prevent infections, and other mechanisms (e.g., phagocytes, natural killer [NK] cells and other innate lymphoid cells [ILCs], the complement system) eliminate microbes. Adaptive immune responses develop later and are mediated by lymphocytes and their products. Antibodies block infections and eliminate microbes, and T lymphocytes eradicate intracellular microbes.
- Interactions between innate and adaptive immunity: Opsonization-Complement-Presentation-Help Antibody-mediated cellular cytotoxicity (ADCC) Monocytes, macrophages and granulocytes can all kill target cells by a process similar to that of CD8 cytotoxic T cells but it is mediated by an antibody-mediated interaction.
- Recognition and receptors: the keys to immunity A- Soluble recognition molecules; Complement-Mannose-binding lectin-Acute phase proteins. B- Cell-associated recognition through pattern-recognition receptors (PRRs) that recognize pathogen associated molecular pattern (PAMP) and damage associated molecular pattern (DAMP). cell membrane, endosome/phagosome and cytoplasm. Some other cell membrane receptor: Virus receptors - Cytokine receptors - Hormone receptors.
- Cellular locations of receptors of the innate immune system. There are five major families of cellular receptors in innate immunity: TLRs, CLRs (C-type lectin receptors), NLRs (NOD-like receptors), RLRs (RIG like receptors), and CDSs (cytosolic DNA sensors).Some receptors, such as certain Toll-like receptors (TLRs) and lectins, are located on cell surfaces; other TLRs are in endosomes. Some receptors for viral nucleic acids, bacterial peptides, and products of damaged cells are in the cytoplasm. NOD and RIG Their full names are complex and do not reflect their functions.
- Cell surface Innate recognition receptors recognize extracellular microorganisms. Toll-like receptors (TLR); Humans have 10 TLRs. TLRs associate with a variety of adaptor molecules that help to convert recognition of microbes into a signal, which activates specific gene transcription within the cell. Cytoplasmic receptors: NOD-like receptors, NOD1 and NOD2 recognize fragments of bacterial cell wall proteoglycans. and are found at high amounts in the epithelial cells that line the gut. Mutations in NOD2 have been found to increase the likelihood of developing Crohn’s disease. Some NOD-like receptors activate the transcription factor NFκB Others activate the inflammasome. In some cases, activation of the inflammasome results in the rapid death of the host cell by a special process known as pyroptosis. RIG-1; Many viruses carry their genetic information in the form of RNA, rather than DNA as do all eukaryotes, switch on the production of interferons and other antiviral proteins.
- - Different TLRs respond to many different, structurally diverse products of microbes. Endosomal TLRs respond only to nucleic acids. - TLRs activate similar signaling mechanisms, which involve adaptor proteins and lead to the activation of transcription factors. These transcription factors stimulate the production of proteins that mediate inflammation and antiviral defense. NF-κB, Nuclear factor κB.
- Phagocytosis and intracellular killing of microbes. Macrophages and neutrophils express many surface receptors that may bind microbes for subsequent phagocytosis. Microbes are ingested into phagosomes, which fuse with lysosomes, and the microbes are killed by enzymes and several toxic substances produced in the phagolysosomes. The same substances may be released from the phagocytes and may kill extracellular microbes. iNOS, Inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.
- Functions of natural killer (NK) cells. A, NK cells kill host cells infected by intracellular microbes, thus eliminating reservoirs of infection. B, NK cells respond to interleukin-12 (IL-12) produced by macrophages and secrete interferon-γ (IFN-γ), which activates the macrophages to kill phagocytosed microbes. Activating and inhibitory receptors of natural killer (NK) cells. A, Healthy host cells express self class I major histocompatibility complex (MHC) molecules, which are recognized by inhibitory receptors, thus ensuring that NK cells do not attack normal host cells. Note that healthy cells may express ligands for activating receptors (as shown) or may not express such ligands, but they are not attacked by NK cells because they engage the inhibitory receptors. B, NK cells are activated by infected cells in which ligands for activating receptors are expressed (often at high levels) and class I MHC expression is reduced so that the inhibitory receptors are not engaged. The result is that the infected cells are killed.
- The functions of complement.
- Classic pathway: antigen–antibody interaction, promote Ca2+-dependent union of three components C1, C2 and C4 to the formation of a ‘convertase’ which splits C3. IgM and some subclasses of IgG when bound to antigen are initiate the classic pathway. Alternative pathway: lack of dependence on calcium ions and the lack of need for C1,C2 or C4. several different molecules can initiate C3 conversion, notably lipopolysaccharides (LPS) and other bacterial products. MBL and other pathways: Mannose-binding lectin can activate C1q so initiate the classic pathway. CRP C-reactive protein, produced in large amounts during ‘acutephase’ responses, binds to bacterial phosphorylcholine and activates C1q. Lytic pathway: Lysis of cells means irreversible leakage of cell important structures leading to cell death. C5-C9 with 10 or more molecules of C9 forming membrane attack complex (MAC) a cylindrical tube when inserted into the membrane of bacteria causes leakage of the contents and death by lysis.
- Pathways of complement activation all of which lead to the production of C3b. C3b initiates the late steps of complement activation, culminating in the formation of a multi-protein complex called the membrane attack complex (MAC), which is a transmembrane channel composed of polymerized C9 molecules that causes lysis of thin-walled microbes. Peptide by-products released during complement activation are the inflammation-inducing C3a and C5a.
- Maturation of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). Mature lymphocytes enter the peripheral lymphoid organs, where they respond to foreign antigens and recirculate in the blood and lymph. Some immature B cells leave the bone marrow and complete their maturation in the spleen.
- Thymus: A two-lobed organ lying in the upper chest, it is largest in early life, atrophy is slower. PCD Programmed cell death, (apoptosis); a process by which cells are induced to die without damage to surrounding tissue. A very high proportion of both B and T cells die in this way because they fail to rearrange their receptor genes properly, or because they threaten to be ‘self-reactive’. Mutations in CD95, a key receptor activating PCD in lymphocytes, are associated with a multi-organ autoimmune disease, illustrating the importance of this pathway in regulating the normal immune response. CD (cluster of differentiation) numbers are used to identify cell-surface antigens that can be distinguished by monoclonal antibodies.
- Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that eliminate extracellular microbes. In cell-mediated immunity, different types of T lymphocytes recruit and activate phagocytes to destroy ingested microbes and kill infected cells
- Classes of lymphocytes. Different classes of lymphocytes in the adaptive immune system recognize distinct types of antigens and differentiate into effector cells whose function is to eliminate the antigens. B lymphocytes recognize soluble or cell surface antigens and differentiate into antibody-secreting cells. Helper T lymphocytes recognize antigens on the surfaces of antigen-presenting cells and secrete cytokines, which stimulate different mechanisms of immunity and inflammation. Cytotoxic T lymphocytes recognize antigens in infected cells and kill these cells. Regulatory T cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity.
- Major histocompatibility complex genes in humans, known as HLA (human leucocyte antigen) genes. Interactions between MHC molecules and T-cell receptors are vital to all adaptive immune responses.
- T-cell receptor (TCR) A complex of T-cell surface molecules, including TCR α plus β, or γ plus δ chains, CD3 and CD4 or CD8, depending on the type of T cell. Costimulatory molecules: T-cell proliferation and cytokine release is governed both by the TCR binding to antigen presented on MHC molecules and by interactions between cell molecules on the membrane of T cells and their ligands on the antigen-presenting cell. Some increase the activation of the T cell while Others inhibit T-cell activation, and act to limit or switch off the immune response. Poly-Ig receptor A molecule found on some epithelial cells that helps to transport antibody into secretions. Adhesion molecules A large range of surface molecules help to hold cells together and facilitate cell–cell interactions or binding to blood vessel walls
- Role of MHC-associated antigen presentation in recognition of microbial antigens by CD4+ and CD8+ T cells. A, Protein antigens of microbes that are endocytosed from the extracellular environment by macrophages and B lymphocytes enter the class II MHC pathway of antigen processing. As a result, these proteins are recognized by CD4+ helper T lymphocytes, whose functions are to activate macrophages to destroy phagocytosed microbes and activate B cells to produce antibodies against extracellular microbes and toxins. B, Protein antigens of microbes that live in the cytoplasm of infected cells enter the class I MHC pathway of antigen processing. As a result, these proteins are recognized by CD8+ cytotoxic T lymphocytes, whose function is to kill infected cells.
- Cooperation between CD4+ and CD8+ T cells in eradication of intracellular infections.
- Characteristics of subsets of CD4+ helper T lymphocytes. A naive CD4+ T cell may differentiate into subsets that produce different cytokines that recruit and activate different cell types and combat different types of infections in host defense. These subsets also are involved in various kinds of inflammatory diseases.
- Isotypes are classified on the basis of their heavy (H) chains; each isotype may contain either κ or λ light chain. Note that IgA consists of two subclasses, called IgA1 and IgA2, and IgG consists of four subclasses, called IgG1, IgG2, IgG3, and IgG4. Most of the opsonizing and complement fixation functions of IgG are attributable to IgG1 and IgG3. The plasma concentrations are average values in normal individuals.
- T-dependent and T-independent antibody responses.
- Effector functions of antibodies
- Tolerance.
- For practical purposes, the main cytokines are classified into families named after one of their functions, although sometimes the terminology is none too clear; e.g. one of the most important macrophage activators is called gamma interferon (IFNγ) because it, and the other interferons, were discovered through their effect in interfering with virus growth. In the same way tumor necrosis factor (TNF), despite its promising name, is chiefly involved in inflammation – and indeed can actually promote cancer. Most of the cytokines are now available in pure form, and are finding their way into medicine, although, as is the case with TNF, it can sometimes be more important to block their action. Binding of TNF to its receptor can trigger either apoptosis or cell activation/survival via the NFκB pathway. TNF is the prototype of a family of about a dozen signaling molecules, some of which are secreted, while others (such as Fas) remain attached to the cell. IL-1 production is regulated by the multimolecular complex called the inflammasome. DD Death domains
- Balance between Th1 and Th2 cell activation determines outcome of intracellular infections. Naive CD4+ T lymphocytes may differentiate into Th1 cells, which activate phagocytes to kill ingested microbes, and Th2 cells, which inhibit classical macrophage activation. The balance between these two subsets may influence the outcome of infections.
- Autoimmunity and hypersensitivity.
- Gell and Coombs classification only covers hypersensitivities involving adaptive immunity, and it is becoming increasingly clear that many of the most common degenerative diseases, such as atherosclerosis and Alzheimer’s disease are caused by chronic activation of innate immunity, especially macrophages, independently of adaptive immunity. Macrophages can be activated by some non-infectious stimuli. Uric acid crystals activate macrophage IL-1 secretion and give rise to the painful symptoms of gout. Chronic macrophage activation by oxidized lipoproteins in blood vessels or the β amyloid protein in brain may cause atherosclerosis and Alzheimer’s disease, respectively. Type I Acute (allergic; anaphylactic; immediate): mediated by IgE antibody together with mast cells (e.g. hay fever). Can also give rise to eosinophil activation, most notably in asthma. Type II Antibody mediated (cytotoxic): mediated by IgG or IgM together with complement or phagocytic cells (e.g. blood transfusion reactions, rheumatic fever, many autoimmune diseases). Type III soluble Antigen–antibody complex mediated: inflammation involving complement, polymorphs, etc. (e.g. Arthus reaction, serum sickness, SLE, chronic glomerulonephritis). Type IV Cell mediated (delayed; tuberculin-type): T-cell dependent recruitment of macrophages, eosinophils, etc. (e.g. tuberculoid leprosy, schistosomal cirrhosis, viral skin rashes, skin graft rejection).
- Allergy and anaphylaxis
- Types of antibody-mediated diseases. Antibodies (other than IgE) may cause tissue injury and disease by: A, binding directly to their target antigens on the surface of cells and in the extracellular matrix (type II hypersensitivity) or B, by forming immune complexes that deposit mainly in blood vessels (type III hypersensitivity). Effector mechanisms of antibody-mediated diseases. Antibodies cause disease by A, inducing inflammation at the site of deposition; B, opsonizing cells for phagocytosis; and C, interfering with normal cellular functions, such as hormone receptor signaling. All three mechanisms are seen with antibodies that bind directly to their target antigens, but immune complexes cause disease mainly by inducing inflammation (A). TSH, Thyroidstimulating hormone.
- Immune complexes, complement and disease
- Mechanisms of T cell–mediated tissue injury (type IV hypersensitivity). T cells may cause tissue injury and disease by two mechanisms. A, Inflammation may be triggered by cytokines produced mainly by CD4+ T cells in which tissue injury is caused by activated macrophages and inflammatory cells; APC, Antigen presenting cell. B, Direct killing of target cells is mediated by CD8+ cytotoxic T lymphocytes (CTLs).
- Chronic and cell-mediated inflammation; giant cell formation.