AUTOIMMUNE DISORDERS Autoimmune disorders occur when individuals develop antibodies to their own cells or cellular material and

these antibodies then attack the individual‟s tissues. The term autoantibodies refer to antibodies formed against self-antigens. Some of these disorders affect single organs or tissues, for example, Hashimoto‟s thyroiditis, and some, such as systemic lupus erythematosus, are generalized. Other examples are rheumatic fever, maesthenia gravis, scleroderma, pernicious anemia, and hyperthyroidism ( Grave‟s disease). The exact process by which autoimmunity develops has not been established. Some individuals may lose their immune tolerance following tissue destruction and release of large numbers of self-antigens into the circulation and subsequently antibodies form. Aging may lead to loss of tolerance to self-antigens. There appears to be a genetic factor involved in autoimmune diseases, given the familial incidence. Self antigens are usually tolerated by the immune system, and there is no reaction to one‟s own antigens. This is fortunate because one cannot avoid exposure to one‟s own antigens. When self tolerance is lost, the immune system is unable to differentiate self from foreign material. The auoantibodies then trigger an immune reaction leading to inflammation and necrosis of tissue. Immunologic Tolerance To function properly, the immune system must be able to differentiate foreign antigens. The ability of the immune system to differentiate self from nonself is called self-tolerance. It is the HLA antigens encoded by MCH genes that serve as recognition markers of self and nonself for immune system. To elicit an immune response,an antigen must first be processed by an antigen-presenting cell (APC), such as macrophage, which then presents the antigenic determinants along with an MCH II molecule to a CD4+ helper T cell. The dual recognition of the MCH-antigen complex by the T-cell receptor (TCR) of the CD4+ helper cell acts loke a security check. Similar recognition checks occur between CD8+ cytotoxic T cells and the class I MCH-antigen complex of tissue cells that have been targeted for elimination. A number of chemical messengers (e.g., interleukins) and costimulatory signals are essential to the activation of the immune responses and preservation of self-tolerance. The mechanisms postulated to explain the tolerant state include central tolerance. Central tolerance refers to the elimination of self-reactive T cells and B cells in the central lymphoid organs (i.e. the thymus for the T cells and the bone marrow for B cells). Peripheral tolerance derives from the deletion or inactivation of autoreactive T cells or B cells and escaped elimination in the entral lymphoid organs. Anergy represents the state of immunologic tolerance to specific antigens. It may take the form of diminished immediate hypersensitivity, delayed-type hypersensitivity, or both. B-Cell Tolerance Loss of self-tolerance with development of autoantibodies is characteristic of a number of autoimmune disorders. For example, hyperthyroidism in Grave‟s disease is due to autoantibodies to the thyroid dtimulating hormone receptor. Several mechanisms are available to filter autoreactive B cells out of the B-cell population:clonal delition of immature B cells in the bone marrow; deletion of autoreactive B cells in the spleen or lymph nodes; functional inactivation or anergy; and recetor editing, a process that changes the specifity of a B-cell receptor when autoantigen is encountered. There is increasing evidence that B-cell tolerance is predominatly due to help from T cells. T-Cell Tolerance The central mechanisms of T-cell tolerance involve the deletion of self-reactive T cells in the thymus. T cells develop from bone marrow-derived progenitor cells that migrate to the thymus, where they encounter self-peptides bound to MCH molecules. T cells that display thehost‟s MCH antigens and TCRs for a nonself antigen are allowed to mature in the thymus (i.e., positive selection). T cells that have high affinity for host cells are sorted out and undergo apoptosis and die in the process (i.e., negative selection). The deletion of self-reactive T cells in the thymus requires the presence autoantigens. Because many autoantigens are not present in the thymus, self reactive T cells may escape the thymus requiring the need for peripheral mechanisms that participate in T-cell tolerance. Several peripheral mechanisms are available to control the responsiveness of the selfreactive T cells in the periphery. Sometimes, the host antigens are not available in the appropriate immunologic form or are separated from the T cells (e.g., by the blood brain barrier) so that corresponding T cells remain immunologically ignorant of their presence. In other cases, the autoreactive T cell encounters its corresponding antigen in the absence of the costimulatory signals that are necessary for its activation. The peripheral activation of T cells requires two signals: recognition of the peptide antigen in association with the MHC molecules on the APCs and a set o secondary costimulatory signals. Because costimulatory signals are not strongly

Virus-encoded antigens expressed on the cell surface can serve as carriers for self antigens. leading to an autoimmune disorder. Breakdown in T-Cell Anergy. disorders of MHC-antigen receptor/complex interactions. More than one defect might be present in each disease. Activation of antigen-specific CD4+ helper T cells requires two signals: recognition of the antigen in association with class II MHC molecules on the surface of the APCs and a set of costimulatory signals provided by the APCs. They may secrete cytokines that suppress the activity of self-reactive immune cells. it seems unlikely that autoimmune disorders arise from a single defect. Another mechanism involves the apoptotic death of autoreactive T cells. For example. This protection can be broken if the normal cells that do not express the costimulatory molecules are induced to do so. T-cell anergy involves the prolonged or irreversible inactivation of T cells under certain conditions. Because T cells regulate the immune response. the body does not produce antibodies against self antigens. These cells are belived to be a distinct subset of CD4+ T cells. partially degraded collagen or enzymatically altered thyroglobulin or gamma globulin may be sufficiently foreign to promote an autoimmune response. the self antigen would appear as a hapten for which an immune response could be induced.expressed on most normal tissues. breakdown of T-cell anergy. Failure of T-Cell-Mediated Suppression.Most normal tissues do not express the costimulatory molecules and thus are protected from autoreactive T cells. Heredity and gender may play a role in the development of autoimmunity. Immunologic cells are undoubtedly involved in the tissue injury that results. TCR recognition of antigen. thus coexpression of the Fas messenger molecule by the same cohort of activated autoreactive T cells may serve to induce their death. There are many ways in which chemical or microbial antigens can be modified to evoke an altered immune response. This type of apoptosis is mediated by an apoptotic cell surface receptor (called Fas) that is present on the T cella and a soluble membrane messenger molecule (Fas ligand) that binds to the apoptotic receptor and activates the death program. The immune system normally recognizes antigen in the context of MHC-antigen complex and TCR interactions. but the precise mechanisms involved in initiating the response is largely unknown. Mechanisms of Autoimmune Disease There are multiple explanations for the loss of self-tolerance and formation of autoantibodies or failure to recognize host antigens as self. The expression of the apoptotic Fas receptor is markedly increased in activated T cells. or MHC antigen presentation-have the potential for initiating an autoimmune response. Thus. Disorders of immune regulatory or surveillance function can result from failure to delete autoreactive immune cells or suppress the immune response. Failure of Self-Tolerance Auoimmunity disorders can result from one or more mechanisms producing loss of selftolerance. Partial degradation of self antigens also may occur. Among the possible mechanisms responsible for development of autoimmune diseases are aberrations in immune cell function or antigen structure. Disorders in MHC-Antigen Complex/Receptor Interactions. If the second costimulatory signal is not delivered. Because of the complexity of the immune system. an increasing ratio of CD4+ helper T cells to CD8+ suppressor T cells may lead to the development of autoimmune disorders. Abberations in any of these three components of the immune response-antigen structure. Release of Sequestered the synovium of persons with rheumatoid arthritis. the encounter of the autorective T cells and their specific target antigens frequently results in anergy. any self antigen that was completely sequestered during development and then reintroduced to the immune system is likely to be regarded as foreign. or in situations in which there is tissue necrosis and local inflammation. Suppressor T cells with the ability to down-regulate the function of the autoreactive T cells are also thought to paly an essential role in the peripheral T-cell tolerance. up-regulation of the costimulator molecule B7-1 has been observed in the central nervous system of persons with multiple sclerosis. For example. and in the skin of persons with psoriasis. Among the proposed mechanisms involved in loss of self-tolerance are failure of T-cell-mediated suppression. Normally. the T cell becomes anergic. molecular mimicry. and superantigens. release of sequesterd antigens. In this case. Autoantigenic drugs and viruses can be complexed to a carrier that is recognized by nontolerant CD4+ helper T cells as foreign. and each mechanism may be involved in more than one disease. Some inductions can occur after an infection.Among the sequestered tissues that could be regarded as foreign are spermatozoa and ocular antigens such as those . The mechanism by which these T cells exert their suppressor function is unclear.

when bound to host proteins or glycoproteins. determination that the immunologic findings are not secondary to another condition. In the spondyloarthritis. a child with chronic or acute history of fever. Post-traumatic uveitis and orchiditis after vasectomy may fall in this category. which can short-circuit the normal sequence of events in an immune response. from a complex to which a humoral response is directed with substantial cross reactivity to the original self protein. For example. Heredity and Gender Genetic factors can increase the incidence and severity of autoimmune diseases. Superantigens are a family of related substances. In the future. Kawasaki disease in children probably has a similar cause. and a macular rash along with high levels of antinuclear antibody has a probable . rheumatoid arthritis and HLA-DR4. causing a massive release of T-cell inflammatory cytokines. or a self antigen from a body tissue has been hidden from the immune system during development. Not everyone exposed to group A B-hemolytic streptococci has an autoimmune reaction. toxic shock syndrome. suggesting that estrogens may play a role in the development of autoimmune disease. antibodies directed against the microorganism cause a classic case of mistaken identity. leading to inappropriate activation of CD4+ helper T cells. primarily IL2 and tumor necrosis factor. Currently. there is a clear relationship between arthritis and a prior bacterial infection. A humoral or cellular response can be mounted against antigenically altered or injured tissue. The reason that only certain persons are targeted for auto immune reactions to a particular selfmimicry molecule may be determined by differences in HLA types. creating an immune process. in which a foreign antigen so closely resembles a self antigen that antibodies produced against the former react with the latter. A number of autoimmune diseases such as SLE occur more commonly in women than men. Molecular Mimicry. Normally. It is imposible that certain autoimmune disorders are caused by molecular mimicry. which leads to inflammation of the heart or kidney. the diagnosis of autoimmune disease is based primarily on clinical findings and serologic testing. Other HLAassociated diseases are Reiter‟s syndrome and HLA-B27. and another‟s HLA type may not. Evidence suggests that estrogens stimulate and androgens suppress the immune response. At least one disease in adults. ismediated by superantigens. it appears that other factors. Instead.found in uveal tissue. Superantigens directly link the class II MCH complex molecules of APCs such as macrophages to TCRs. Because autoimmunity does not develop in all persons with genetic predisposition.” interact to precipitate the altered immune state. however. they are able to interact with a TCR outside the normal antigen-binding site. and an uncontrolled proliferation of T cells. In rheumatic fever and acute glomerulonephritis.α (TNF – α). a protein in the cell wall group A B-hemolytic streptococci has considerable similarity with antigens in heart and kidney compared with 7% of persons without the disease. The molecular basis for these associations is unknown. including staphylococcal and streptococcal exotoxins. Superantigens do not require processing and presentation of antigen by APCs to induce a T-cell response. only a small percentage of the T-cell population (0. For example. a chemical substance. and the lack of other identified causes for the disorder. superantigens can interact with 5% to 30% of T cells. The HLA type determines exactly which fragments of a pathogen are displayed on the cell surface for presentation to T cells. Certain drugs. arthritis. and systemic lupus erythematosus (SLE) and HLA-DR3. it is likely that autoimmune disorders will be diagnosed by directly identifying the genes responsible for the condition. The antihypertensive agent methyldopa can bind to surface antigens on red cells to induce an antibody-mediated hemolytic anemia. 90% of persons with ankylosing spondylitis carry the HLA –B27 antigen. combined with the inherited HLA-B27 antigens. The event or events that trigger the development of an autoimmune response are unknown. which is thought to assist in the induction of n autoimmune response. Superantigens. respectively. estrogen stimulates a DNA sequence that promotes the production of interferon –γ. as shown by the familial clustering of several autoimmune diseases and the observation that certain inherited HLA types occur more frequently in persons with a variety of immunologic and lymphoproliferative disorders. such as a “trigger event.01%) is stimulated by the presence of proecesed antigens on the surface of macrophages. for example. The basis for most serologic assays is demonstration of antibodies directed against tissue antigens or cellular components. After infection. It has been suggested that the trigger may be a virus or other microorganism. For example. Diagnosis and Treatment of Autoimmune Disease Suggested criteria for determining that a disorder is an autoimmune disorder include evidence of an autoimmune reaction. One individual‟s HLA may bind self-mimicry molecules for presentation to T cells.

The generation of polyclonal T-cell cytolytic activity is impaired.g. is also an option in some severe cases of autoimmunity. T cells. Moreover. Healthy persons sometimes have low titers of antibody against cellular and tissue antigens. Pathophysiology SLE is an autoimmune disorder characterized by multisystem microvascular inflammation with the generation of autoantibodies. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. hormonal. both innate and acquired. Whether polyclonal B-cell activation or a response to specific antigens exists is unclear. Management depends on disease severity and organ involvement. Helper (CD4+) T cells are increased. including genetic. leading to complement activation and inflammation. the effector mechanism involved.. SLE can affect any organ system. Enzyme-linked immunosuppressant assay (ELISA) c. which binds to the patient‟s antibody and forms a visible reaction.e. Although the specific cause of SLE is unknown. apoptosis. Finally. Immune complexes form in the microvasculature. and dendritic cells. Notably. The redistribution of cellular antigens during necrosis/apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes. immunoglobulins. Many immune disturbances. A lack of immune tolerance is observed in animal lupus models. 1:100 dilution). infliximab) for RA and Crohn disease are the first new treatments for autoimmunity approved by the FDA in the past 20 years. fixed cells for the detection of antinuclear antibodies). Example: Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean manifestations and follows a relapsing and remitting course. Cytotoxic T cells and suppressor T cells (which would normally down-regulate immune responses) are decreased. and complement proteins at these sites. kidneys. Periodic follow-up and laboratory testing are imperative to detect signs and symptoms of new organ-system involvement and to monitor the response or adverse reactions to therapies. but the titers usually are far lower than in patients with autoimmune disease. The binding of the patient‟s antibody to antigen-coated particles causes a visible agglutination reaction. This is called a positive titer. interferon-β for multiple sclerosis and TNF α antibodies (e. through the use of plasmapheresis. Particle agglutination The rationale behind each of these methods is similar: the patient‟s serum is diluted and allowed to react with an antigen-coated surface (i. treatment should focus on the mechanism underlying the autoimmune disorder. research into the development of vaccines to target critical pathways in the emergence of autoimmune responses is ongoing.g. and environmental factors. but much of the pathology involves B cells. In active SLE. dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens. Serum antinuclear antibodies (ANAs) are found in nearly all individuals with active SLE. occur in SLE One longstanding proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance. joints. Recent genetic studies point to disruptions in lymphocyte signalling. and the magnitude and chronicity of the effector processes. Antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis of SLE. and DNA methylation. and nervous system The diagnosis of SLE must be based on the proper constellation of clinical findings and laboratory evidence. blood cells.. Subsequently. the patient‟s serum is serially diluted until it no longer produces a visible reaction (e. this process has been confirmed by demonstration of complexes of nuclear antigens such as DNA. but mainly involves the skin. clearance of complement and immune complexes. The detection of autoantibodies in the laboratory usually is accomplished by one of three methods: a. Recent reports . Treatment of autoimmune disease is based on the tissue organ that is involved. Indirect fluorescent antibody assays (IFA) – b. antibody-antigen complexes deposit on the basement membranes of skin and kidneys. Purging autoreactive cells from the immune repertoire. Corticosteroids and immunosuppressive drugs may be used to arrest or reverse the downhill course of some autoimmune disorders. interferon response. whole.. multiple factors are associated with the development of the disease.diagnosis of SLE. For most serologic assays. racial. Particle agglutination assays are much simpler. Recent research has focused on the cytokines involved in the inflammatory response that accompanies many of the autoimmune disorders. Many clinical manifestations of SLE are mediated via circulating immune complexes in various tissues or the direct effects of antibodies to cell surface components. In the cases of IFA and ELISA. a second „labeled” antibody is added. Ideally.

the annual incidence of SLE averages 5. Although the prevalence of SLE is high in black persons in the United Kingdom. The prevalence of SLE is approximately 40 per 100. Interestingly. the prevalence of SLE varies. B8. The highest prevalences have been reported in Italy. Epidemiology United States statistics In the United States. The frequency of SLE could be increasing due to milder forms of the disease that are now being recognized. International statistics Worldwide. In the United States. including to protein regions homologous to nuclear antigens. Viruses may stimulate specific cells in the immune network. different prevalence rates occur among people of the same race in different geographical locations. the disease is rarely reported among blacks who live in Africa. Minnesota. SLE frequently starts in women of childbearing age. Photosensitivity is clearly a precipitant of skin disease. Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV). Environmental and exposure-related causes of SLE are less clear. suggesting a role for hormonal factors in the pathogenesis of the disease. Arizona. Studies of human leukocyte antigens (HLA) reveal that HLA-A1. versus 100 per 100. Silica dust and cigarette smoking may increase the risk of developing SLE. The incidence of SLE in black women is approximately 4 times higher than in white women.000 Hispanic persons in Nogales. In general. suggesting that there may be an environmental trigger as well as a genetic basis for their disease. transcription factors. and make antibodies to retroviruses. and other early components) are also associated with an increased risk of SLE. have increased circulating EBV viral loads. Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity. approximately 250.000 Americans have SLE. The contrast between low reported rates of SLE in Africa and high rates among black women in the United Kingdom suggests the importance of environmental influences. According to a 2008 report from the National Arthritis Data Working Group. Martinique.000 population. C2. the prevalence of SLE appears to vary by race. and acute lupus flares often follow bacterial infections. and DR3 are more common in persons with SLE than in the general population. followed by Asians. SLE is more common in men with .000 whites in Rochester. black women have a higher rate of SLE than any other race. However. with higher rates reported among black and Hispanic people. The risk of SLE development in men is similar to that in prepubertal or postmenopausal women. The reported prevalence is 52 cases per 100. Administration of estrogen to postmenopausal women appears to increase the risk of developing SLE. her daughter's risk of developing the disease has been estimated at 1:40 and her son's risk is 1:250. sex-. Breastfeeding is associated with a decreased risk of developing SLE.000 population. multiple genetic predispositions and geneenvironment interactions have been identified (see chart below). Spain. If a mother has SLE. and the use of exogenous hormones has been associated with lupus onset and flares. Race-. and signaling variations also point to a central role for neutrophils Etiology Although the specific cause of SLE is unknown. and age-related demographics Worldwide.1 per 100. The results of one study suggest that low vitamin D levels increase autoantibody production in healthy individuals. vitamin D deficiency was also linked to B-cell hyperactivity and interferonalpha activity in patients with SLE. Chronic infections may induce anti-DNA antibodies or even lupuslike symptoms. then white women. and the United Kingdom Afro-Caribbean population. SLE is also more frequent in Asian women than in white women. The presence of the null complement alleles and congenital deficiencies of complement (especially C4. Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations. black women are 4 times more likely to have SLE than white women. A genetic predisposition is supported by the 40% concordance among monozygotic twins. The frequency of SLE varies by race and ethnicity. This complex situation perhaps explains the variable clinical manifestations in persons with SLE. At least 35 genes are known to increase the risk of SLE.pointing to important roles of interferon alpha.

The LUMINA study group examined SLE among black. and advances in general medical care. Infections account for 29% of all deaths in these patients. white. The prevalence of SLE is highest among women aged 14-64 years. HIV infects the T helper cell because it has the protein CD4 on its surface. Manzi et al reported that women aged 35-44 years with SLE were 50 times more likely to develop myocardial ischemia than healthy Framingham control women. and the 15-year survival rate is approximately 80%. Mortality in the first few years of illness is typically from severe SLE disease (eg. In 1976. SLE does not have an age predilection in males. also supporting a hormonal hypothesis. and features of the disease vary greatly between individuals. Mortality in patients with SLE has decreased over the past 20 years. inflammatory mediators. Prognosis SLE carries a highly variable prognosis for individual patients. SLE often waxes and wanes in affected individuals throughout life. genotype XXY) than in men without the syndrome. the average 10-year survival rate exceeds 90%. renal. The influence of race on prognosis has been widely debated. the female-to-male ratio falls. which HIV uses to attach itself to the cell before gaining entry. Onset of SLE is usually after puberty. This is why the T helper cell is sometimes referred . according to the Centers for Disease Control and Prevention.Klinefelter syndrome (ie. They include endothelial dysfunction. Example: ACQUIRED IMMUNODEFICIENCY SYNDROME HIV infects cells in the immune system and the central nervous system. A correlation between age and incidence of SLE mirrors peak years of female sex hormone production. Decreased mortality rates associated with SLE can be attributed to earlier diagnosis (including milder cases). and to carefully plan pregnancies. with 20% of all cases diagnosed during the first 2 decades of life. A large reduction in the number of T helper cells seriously weakens the immune system. and Hispanic patients in the United States (including Puerto Rico) and reported that both disease activity and poverty predicted higher mortality among racial and ethnic minorities. Educate patients with SLE regarding aggressive lipid and blood pressure goals to minimize the risk of coronary artery disease. The disease course is milder and survival rate higher among persons with isolated skin and musculoskeletal involvement than in those with renal and CNS disease. typically in the 20s and 30s. by coordinating the actions of other immune system cells. The natural history of SLE ranges from relatively benign disease to rapidly progressive and even fatal disease. Yet. Prior to 1955. One of the main types of cells that HIV infects is the T helper lymphocyte. Encourage them to receive non live vaccines during stable periods of disease. the 5-year survival rate in SLE was less than 50%. to quit smoking. CNS. and dyslipidemia. Urowitz first reported bimodal mortality in early versus late SLE. although it should be noted that among older adults. but may reflect detection bias of severe cases only. Advise them regarding their hightened risks for infection and cardiovascular disease. The presence of lupus nephritis may increase these risks Causes of accelerated coronary artery disease in persons with SLE are likely multifactorial. The female-to-male ratio peaks at 11:1 during the childbearing years. Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light. including fever. Instruct patients with SLE to seek medical care for evaluation of new symptoms. ranging from 60-70%. one third of SLE-related deaths in the United States occur in patients younger than 45 years. Patient Education Stress the importance of adherence with medications and follow-up appointments for detection and control of SLE disease. corticosteroid-induced atherogenesis. however. noting that SLE-related deaths usually occur within the first 5-10 years of symptom onset. Ten-year survival rates in other countries within Asia and Africa are significantly lower. or cardiovascular involvement) or infection related to immunosuppressive treatment. Late deaths (after age 35 years) are generally from myocardial infarction or stroke secondary to accelerated atherosclerosis. making this a serious issue despite declining overall mortality rates. improvement in disease-specific treatments. These cells play a crucial role in the immune system. currently.

leading eventually to an AIDS diagnosis. but is very active in the lymph nodes. Once it has found its way into a cell. Treatment can stop HIV from damaging the immune system. therefore. which can then go on to infect other cells. this differs slightly between adults and children under five. at which point the individual is said to have progressed to AIDS. an AIDS diagnosis is based on having any stage 4 condition and/or a CD4 percentage less . HIV mutates and becomes more pathogenic. the immune system fails and symptoms develop. In adults and children (aged 5 or over) the progression to AIDS is diagnosed when any condition listed in clinical stage 4 is diagnosed and/or the CD4 count is less than 200 cells/mm3 or a CD4 percentage less than 15. the CD4 count continues to decline to very low levels. HIV infection can generally be broken down into four distinct stages: primary infection. Research has shown that HIV is not dormant during this stage. STAGE 1 : Primary HIV infection This stage of infection lasts for a few weeks and is often accompanied by a short flu-like as a CD4+ lymphocyte. in HIV-infected individuals not receiving treatment or on treatment that is not working. Treatment for the specific infection is often carried out. This test which measures HIV RNA (HIV genetic material) is referred to as the viral load test. Unless HIV itself can be slowed down the symptoms of immune suppression will continue to worsen.  The body fails to keep up with replacing the T helper cells that are lost. symptomatic HIV infection. but the underlying cause is the action of HIV as it erodes the immune system. The level of HIV in the peripheral blood drops to very low levels but people remain infectious and HIV antibodies are detectable in the blood. HIV-infected individuals on treatment usually remain clinically asymptomatic. clinically asymptomatic stage. However. In children younger than five. an indication that the immune system is deteriorating. HIV produces new copies of itself. This stage of HIV infection is often characterised by multi-system disease and infections can occur in almost all body systems. In up to about 20% of people the HIV symptoms are serious enough to consult a doctor. This process is known as seroconversion. and it has an important role in the treatment of HIV infection. During this stage there is a large amount of HIV in the peripheral blood and the immune system begins to respond to the virus by producing HIV antibodies and cytotoxic lymphocytes. This is thought to happen for three main reasons:   The lymph nodes and tissues become damaged or 'burnt out' because of the years of activity. so antibody tests will show a positive result. Without treatment. Antiretroviral treatment is usually started once an individuals CD4 count (the number of T helper cells) drops to a low level. is free from major symptoms. in other words stronger and more varied. but as the immune system deteriorates the symptoms worsen. A clinical criteria is used by WHO to diagnose the progression to AIDS. STAGE 4 : Progression from HIV to AIDS As the immune system becomes more and more damaged the individual may develop increasingly severe opportunistic infections and cancers. STAGE 3 : Symptomatic HIV infection Over time the immune system becomes severely damaged by HIV. STAGE 2 : Clinically asymptomatic stage This stage lasts for an average of ten years and. although there may be swollen glands. leading to more T helper cell destruction. Over time. Initially many of the symptoms are mild. It can take several years before the CD4 count declines to the point that an individual needs to begin antiretroviral. HIV infection leads to a severe reduction in the number of T helper cells available to help fight disease. and progression from HIV to AIDS. but the diagnosis of HIV infection is frequently missed. Symptomatic HIV infection is mainly caused by the emergence of certain opportunistic infections that the immune system would normally prevent. as its name suggests. A test is available to measure the small amount of HIV that escapes the lymph nodes. The number of T helper cells is measured by having a CD4 test and is referred to as the CD4 count. If an HIV antibody test is done before seroconversion is complete then it may not be positive.

which may be used to guide medical decision making.than 20 (children aged 12-35 months) and a CD4 percentage less than 25 (children less than 12 months). The criteria for diagnosing AIDS may differ depending on individual country guidelines. Clinical Stage I:  Asymptomatic  Persistent generalized lymphadenopathy Clinical Stage II: Moderate unexplained* weight loss (under 10% of presumed or measured body weight)** Recurrent respiratory tract infections (sinusitis. medical facilities are sometimes poorly equipped and tests to measure CD4 count and viral load are unavailable. tonsillitis. System                  Examples of Infection/Cancer Pneumocystis jirovecii Pneumonia (PCP) Tuberculosis (TB) Kaposi's Sarcoma (KS) Cryptosporidiosis Candida Cytomegolavirus (CMV) Isosporiasis Kaposi's Sarcoma Cytomegolavirus Toxoplasmosis Cryptococcosis Non Hodgkin's lymphoma Varicella Zoster Herpes simplex Herpes simplex Kaposi's sarcoma Varicella Zoster Respiratory system Gastro-intestinal system Central/peripheral Nervous system Skin WHO clinical staging of HIV disease in adults and adolescents (2006 revision) In resource-poor settings. Examples of opportunistic infections and cancers The table below shows examples of common opportunistic infections and cancers and the body systems that they occur in. otitis media. In this case. another method to determine whether an individual should begin treatment is used. The World Health Organization (WHO) developed a staging system for HIV disease based on clinical symptoms. pharyngitis) Herpes zoster Angular chelitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections Clinical Stage III: Unexplained* severe weight loss (over 10% of presumed or measured body weight)** Unexplained* chronic diarrhoea for longer than one month Unexplained* persistent fever (intermittent or constant for longer than one month) Persistent oral candidiasis Oral hairy leukoplakia              .

bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis Chronic isosporiasis Disseminated mycosis (extrapulmonary histoplasmosis. antibodies to HIV bind to HIV antigens. When EIA is reactive. pneumonia. In an EIA test. Diagnosis. or positive. The test is considered reactive. is measured. and negative. if there is no color. indicating the amount of HIV antibodies found. bacteraemia) Acute necrotizing ulcerative stomatitis. mutually monogamous sexual relationships between two uninfected partners are the best way to avoid HIV infection and other STDs. EIA tests high false-positive rates. coccidiomycosis) Recurrent septicaemia (including non-typhoidal Salmonella) Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy Prevention.the person is considered to be infected by HIV. When a serum antibody test result is reactive or borderline by EIA and positive by Western blot. Diagnostic Methods The diagnostic methods used for HIV infection include laboratory methods to determine infection and clinical methods to evaluate progression of the disease. The Western blot test therefore is essential to determine which persons withn positive EIA tests are truly infected. empyema. followed by a confirmatory test. pyomyositis. The most accurate and inexpensive method for identifying HIV is the HIV antibody test. A substrate is then added from which the enzyme produces a color reaction. the Western blot assay which is performed if the EIA is positive. genital or anorectal of more than one month‟s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea. The HIV antibody test procedure consists of screening with an enzyme immunoassay (EIA). the person is not infected with HIV. also known as enzymelinked immunosorbent assay (ELISA).5 billion/l) and/or chronic thrombocytopenia (below 50 billion/l) Clinical Stage IV HIV wasting syndrome Pneumocystis pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection (orolabial. neutropenia (below 0. and the Western blot is negative. The antigen –antibody complex is then detected using an antihuman immunoglobulin G (IgG) antibody conjugated to an enzyme like alkaline phosphatase. if color is produced.g. bone or joint infection. misinfrormation can be generated by EIA testing alone because there are many situations that can produce a false-positive or a false-negatiev ELISA result. Both tests areimportant because in someinstitution.                      . when blood is added. The Western blot is more sensitive assay that looks for presence of antibodies to specific viral antigens. meningitis. or non reactive. and Treatment Because there is no cure for HIV or AIDS.    Pulmonary tuberculosis Severe bacterial infections (e. Color development. The EIA detects antibodies produced in response to HIV infection. gingivitis or periodontitis Unexplained* anaemia (below 8 g/dl). EIA tests are used first because they are less expensive and are quicker to perform. Avoiding recreational drug use and particularly avoiding the practice of using syringes that may have been used by another person are important to HIV prevention. Abstinence or long term. thus samples that are repeatedly reactive are tested by a confirmatory test such as Western blot. adopting a risk free or low risk behavior is the best protection against the disease.

Persons who are symptomatic may need to be seen more frequently. Approximately &0% have IgA deficiency. Intellectual development is normal at first but seems to stop at the 10-year level in many of these children. In general. block receptors on the CD4+ Tcells so that the HIVcannot attach to the CD4+ T cell. poor muscle coordination) and the appearance of telangiectases (i.New technology has led to new forms of testing like the oral test. Nucleoside reverse transcriptase inhibitors 2.prevent the HIV DNA from being integrated into the host genome. including reduced levels of IgA. Routine follow-up care of a stable. The ataxia usually goes unnoticed until the toddler begins to walk. Children with ataxia-telangiectasia have deficiencies in both cellular and humoral immunity. the telangiectases develop thereafter.e. this syndrome is heralded by worsening cerebellar ataxia (i... IgE. . Non nucleoside reverse transcriptase inhibitors (work by binding to the reverse transcriptase enzyme so that it cannot copy the virus‟s RNA into DNA) 4. antiviral therapies are prescribed to slow the progression to AIDS and improve the overall time of persons with HIV infection. and IgG2. entry inhibitors. There are currently five different types of HIV antiretroviral medications: 1. hepatic. and the new rapid blood test. which the EIA and Westren blot tests detect. PCR is useful in diagnosing HIV infection in infants born to infected mothers because these infants have their mother‟s HIV antibody regardless of whether or not the infants are infected Early Management After HIV infection is confirmed. often referred to s HAART. The gene normally repairs double-stranded DNA breaks.e. This evaluation should include a history and physical examination and baseline laboratory tests. Pathophysiology AT is caused by a defect in the gene responsible for recognizing and correcting errors in duplicating DNA when cells divide. Death from malignant lymphoma is common. Treatment Because different drugs act on different stages of the replication cycle. immunologic. asymptomatic HIV infected patient should include a history and physical examination along with CD4+ cell count and viral loading testing every 3 to 4 months. the degree of immunodeficiency based on the CD4+ cell count. Vaccine that would prevent HIV infection B. Ther is increased susceptibility to recurrent upper and lower respiratory tract infections (particularly those caused by encapsulated bacteria) and an increased risk for the development of malignancies. The goal of HAART is sustained suppression of HIV replication. Therapeutic interventions are determined by the level of disease activity based on the viral load. optimal treatment includes combination of at least three drugs. lesions consisting of dilated capillaries and arterioles) on the skin and conjunctival surfaces. It is an autosomal recessive disorder that is thought to result from the mutation of chromosome 11 (11q22-23). especially on the skin surfaces exposed to the sun. endocrinologic. and the appearance of specific opportunistic infections. baseline evaluation should be done. resulting in an undetectable viral load and an increasing CD4+ cell count. integrase inhibitors. Vaccine for people already infected with HIV Example:Ataxia-Telangiectasia Ataxia-telangiectasia is a complex syndrome of neurologic. absolute lymphonemia. Fusion inhibitors (prevent HIV from fusing with the CD4+ cell. As the name implies. The ataxia progresses slowly and relentlessly to severe disability. and approximately half also have an IgG subclass deficiency. Nucleotide analog reverse transcriptase (both act by blocking the elongation of the DNA cahin by stopping more nucleosides from being added) 3. thus blocking the the HIV from inserting its genetic information into the CD4+ T cell HIV drug under investigation: A. home testing kits. Protease inhibitors (bind to the protease enzyme and inhibit its action) 5.including fusion inhibitors as well as receptor blockers. B. Polymerase chain reaction (PCR) is a technique for detecting HIV DNA. and cutaneous abnormalities. and a decrease in the ratio of CD4+ helper T cells to CD 8+ suppressor T cells. PCR detects the presence of the virus rather than the antibody to the virus. There are currently 2 types of vaccine being examined: A.

Physical and occupational therapy may help maintain flexibility. it identifies the damage at several checkpoints in the cell division cycle. which they are unable to repair. Recently deferoxamine was shown to increase the stability of A-T cells and may prove to be an effective treatment for the disorder. if it can't repair the damage. discovered in 1995. because X-rays induce double-stranded DNA breaks. It is also recommended that heterozygote family members are regularly monitored for cancers.The gene. particularly lymphomas and leukaemia. it commits suicide through programmed cell death (apoptosis). This allows cells with damaged DNA to reproduce. female ATM patients have a twofold higher risk of developing breast cancer. the pathways that control these processes are defective. often before age 50. Some physicians recommend low doses of chemotherapy to reduce the risk of cancer but this is controversial.[11] . These downstream genes include tumor suppressor proteins p53 and BRCA1. ataxia-telangiectasia mutated (ATM). is on chromosome 11 (11q 22-23) Normally. In A-T. Antibiotics are used to treat infections. It tries to repair the damage. The ATM gene plays a critical role in this process. and DNA repair protein NBS1. For example. It mobilizes several other genes to try to repair the DNA damage or destroy the cell if they can't repair it. resulting in chromosome instability. abnormalities in genetic recombination. Speech therapy may also be needed. radiotherapy and chemotherapy are rarely used. High-dose vitamin regimens may also be used. People with A-T have an increased incidence (probably 1% risk per year) of tumours. but due to sufferers' hyper-sensitivity to ionising radiation. ATM patients are particularly sensitive to X-rays. Gamma-globulin injections may be given to help supplement a weakened immune system. checkpoint kinase CHK2. They are also particularly susceptible to cancers that result from double-stranded DNA breaks. when a cell tries to duplicate damaged DNA. Management Treatment is symptomatic and supportive. and. and an absence of programmed cell death. checkpoint proteins RAD17 and RAD9.

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