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Innate immune effector mechanisms – Complement • Complement: – complex group of plasma proteins that are pre-formed (not made in response to infection) – found in serum and body fluids – produced mainly by liver cells – can be thought of as a form of innate humoral immunity • Activation of complement results in a cascade of molecular events, which results in: – enhanced phagocytosis of microbes – recruitment of inflammatory cells – direct lysis of bacteria • There are three different activation pathways for complement: – alternative pathway (induced by direct interactions with molecules in the surface of pathogens) – classical pathway (antibody-mediated) – lectin pathway (induced by the mannose-binding protein, an acute-phase reactant) • The poorly-named alternative pathway is perhaps the most active and important means of activating complement, in that it can act early in infection, before the stimulation of other responses. • Some complement components are activation/proteolytic enzymes. • Other complement components are membranebinding proteins that act as opsonins. • Other complement components are mediators of inflammation. • Still others form part of what is called the membrane-attack complex, which can lyse microbes. • All three complement pathways intersect at the point of having some enzyme (a C3-convertase) that can cleave a molecule called C3 into C3b and C3a, as well as an enzyme that can cleave C5 (C5 convertase). • C3b is a potent opsonin. • C3a and C5a are peptide mediators of inflammation. • C5b forms part of the membrane attack complex Innate immune effector mechanisms – Macrophagedriven inflammatory responses, Acute Phase Response Antibody Effector Functions • Antibodies can exert a wide variety of effector functions, including helping induce complement activation via the classical pathway, enhancing phagocytosis, as well as arming NK cells in ADCC • In addition to this, antibody molecules can carry out a wide range of biological functions. Antibodies can directly neutralize viruses, bacteria, or bacterial toxins The different immunoglobulin isotypes have different biological properties, and are selectively distributed throughout the body: • IgM is found primarily in blood, and is very efficient at activating complement. • IgE can activate mast cell degranulation, inducing allergic responses. • IgA is readily transported across epithelial barriers and serves as the primary immunoglobulin type in gut and mucosal surfaces. IgA also is found in colustrum and breast milk. • IgG is the only isotype that is transported across the placenta. Together, these passively-transferred antibodies provide a significant level of immune protection in the newborn, as newborn humans cannot produce their own antibodies for some time after birth: Cancer - interactions with the immune system • Cancer refers to a collection of diseases characterized by: – abnormal cellular proliferation – invasion of normal tissues • Cancers are primarily diseases of older people. • In developed countries where life expectancy has increased significantly over the last century, due to control of infectious disease, cancer is a significant clinical problem. • Nearly a quarter of deaths in developed countries, such as the United States, are due to cancer. 5 2 10 4 1 3 8 7 1 9 3 5 8 All Cancers, White Males, 1950-1994 from NIH-NCI Atlas of Cancer Mortality Melanoma, White Males, 1950-1994 Lung, White Males, 1950-1994 • Cancer cells are similar enough to normal cells to make eliminating cancer quite difficult. • Commonly used approaches, such as surgery, radiation therapy and cytotoxic drugs either affect normal, non-cancerous cells, or cannot eliminate all tumor cells, making treatment difficult. • Tumors arise from mutations that result in uncontrolled growth. • In particular, mutations that subvert mechanisms normally involved in normal controls on cell division and cellular survival can result in cancer. • Examples of this are mutations in which proto-oncogenes are activated, or tumor suppressor gene function is lost. • These mutations provide a selective growth advantage to nascent tumor cells, and these cells then accumulate further mutations, which give them a great growth and viability advantage. • The cumulative effect of these multiple mutations is malignant transformation . • Therefore, cancer arises from a single cell that has accumulated the most optimal set of mutations. mutations acquired during the development of colorectal cancer • Cancer can arise from exposure to carcinogens: – mutagenic chemicals – radiation (ultraviolet light) • Certain viruses have the potential to transform cells: oncogenic viruses • Such viruses account for a significant minority of cancers. • Oncogenic viruses can promote cancer by a variety of means, including virus-encoded homologues that mimic or subvert human genes involved in: – cellular activation (EBV LMP1 ~ CD40 on B cells) – cellular growth control (HPV E6 & E7; cytokine homologues) – induction of resistance to apoptosis (bcl2 homologues) • Oncogenic DNA viruses usually induce long-term infection in their host cells, and override normal growth/viability control in these cells. • Simpler viruses, such as retroviruses, can induce cancer by inserting into a host cell chromosome in the wrong place, resulting in uncontrolled host gene expression, since these viruses are inserted into the host chromosome as proviral DNA. • Finally, some viruses may cause cancer by inducing elevated levels of cellular proliferation and replacement, enhancing the chances of a genetic error that could result in cancer. • Immune surveillance theory: the theory that the immune system plays a significant role in tumor surveillance. • Based on increasing knowledge of immune function, and the understanding that immune responses could distinguish between self and non-self, and could exert cytotoxic responses that could kill tumor cells. • A correlate of this theory is that cancer results from some failure in immune surveillance. • Does immune surveillance play a central role in cancer control? • People who have immune deficiency syndromes do not show a significant increase in the most common cancers. • While there is a marked increase in cancer in such immunedeficient people, they tend to develop certain rare cancers (Kaposi’s sarcoma, lymphoid malignancies), most of which are virus-associated cancers. • Therefore, immune responsiveness almost certainly plays a key role in controlling tumor cell growth and development in the case of virus-associated cancers, by controlling virusinfection by normal means (CTL, NK cells, etc). • However, loss of immune surveillance may not be as important in the genesis of more common forms of cancer. • Curiously, tumor cells are easily killed by cytotoxic T cells that are responding to allogeneic differences: tumor cells that are not of the same MHC type as the host are readily killed by normal cellular immune responses • Therefore, tumor cells are not inherently resistant to cytotoxic effector cells. • Tumor cells are not killed in an animal that shares MHC type with the tumor cell because the tumor cell is not antigenic. • Since the genetic changes that occur in tumor cells are slight (in tumors not associated with virus infection), the host immune system may not be able to distinguish these cells, antigenically, from other cells in the body. • Tumor antigens are molecules expressed on tumors that can elicit an immune response • Tumor antigens : – tumor-specific antigens - antigens that are unique to a given tumor – tumor-associated antigens - antigens that are widely expressed on tumor cells, but which are not unique (these same antigens may be expressed on normal cells of other tissue types, or at other stages of development) • Tumor-specific antigens are often seen in chemicallyinduced tumors, in which a mutagen has induced a change that is sufficiently large to result in a clear antigenic change. • Some tumor-associated antigens are products of re-activated embryonic genes, which are not normally expressed on mature cells. • In other cases, tumor-associated antigens represent overexpression of normal molecules that are expressed at much lower levels in non-malignant cells: • It is possible that there is some level of immune response initiated against a nascent tumor clone - as the progeny of the original tumor cells accumulate further mutations, some rare cells evolve the ability to evade host immune responses. • Some tumor cells have been seen to have lost expression of MHC class I genes, which would allow them to evade CTL killing. • However, such cells would be more susceptible to NK cell killing. • In any case, it is possible that enhancing anti-tumor immune responses, either humoral (antibody) or cellular (CTL, NK), might allow control of tumor cell growth. • Many experimental immune-based therapies are being examined for their ability to result in anti-cancer effects. • For instance, monoclonal antibodies directed to tumor antigens, and conjugated to toxins or radioactive tags, have been utilized in experimental treatment: • Other approaches include attempts to enhance anti-tumor T cell responses by enhancing the effectiveness of tumor antigen presentation to potentially cytotoxic cells: There are tumors of immune system cells, and these mirror the various stages of these cells’ development: • Chromosomal translocations can result in the uncontrolled expression of a normal gene that is involved in inducing cellular proliferation or viability (myc proto-oncogene), inducing the overexpression of that gene, resulting in uncontrolled cellular growth: c-myc:Ig gene translocation. This chromosomal translocation is commonly seen in Burkitt’s lymphoma, including AIDSassociated Burkitt’s lymphoma and SNCCL. This genetic lesion, believed to occur during the process of Ig isotype switching, results in the transcriptional activation of the translocated c-myc oncogene, contributing to lymphomagenesis. • Isotype switching - change in the type of H-chain that is used by a given B cell: Transplantation and the immune system • An increasing number of diseases are being treated by transplantation: * * in the US * • A significant clinical problem in tissue transplantation has been the development of immune responses to the grafted tissue: transplant rejection: • Another potential transplant-associated problem are anti-recipient responses by immune cells in the grafted tissue to the host (graft vs host disease – GVH). • A lot of research in immunology was driven by the need to understand transplantation rejection. • In fact, MHC, or major histocompatibility complex molecules, were first studied because they were associated with graft rejection, and only later were seen to play key roles in the generation of immune responses. • It was seen that matching MHC type between donor tissues and the host resulted in decreased rejection, and in significantly increased graft survival: • Autograft - tissue transplanted from one site to another on the same person: not rejected. • Syngeneic transplants transplants between genetically-identical animals (twin humans or inbred mouse strains): not rejected • Allograft - transplants between genetically different individuals: rejected • The exception to this was pregnancy, in which the fetus, which is genetically nonidentical to the mother (fetal allograft) is not rejected (why this is so is still not completely clear). • Graft rejection was seen to involve several immune mechanisms. • Subjects who had pre-formed antibodies that reacted with antigens on the graft often showed a very rapid antibodymediated form of rejection - hyperacute rejection: • Other forms of graft rejection were mediated by host T cells that were stimulated by foreign antigens on the graft to become activated and develop into effector cells. • This form of rejection, acute rejection, is due to alloreactions to graft MHC class I and class II molecules that are different from those of the host. • The development of effective immunosuppressive drugs has been of great clinical importance in prolonging graft survival. • One of the most important immunosuppressive drugs is cyclosporin, which is a potent T cell-inhibitory drug. • Cyclosporin inhibits signaling induced following ligation of the TCR complex, preventing induction of IL-2 and IL-2 receptor gene expression: • This cyclosporin-mediated inhibition of IL-2 and IL-2 receptor gene expression effectively inhibits T cell activation and proliferation in response to antigen: