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

these antibodies then attack the individuals tissues. The term autoantibodies refer to antibodies formed against self-antigens. Some of these disorders affect single organs or tissues, for example, Hashimotos thyroiditis, and some, such as systemic lupus erythematosus, are generalized. Other examples are rheumatic fever, maesthenia gravis, scleroderma, pernicious anemia, and hyperthyroidism ( Graves 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 ones own antigens. This is fortunate because one cannot avoid exposure to ones 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 Graves 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 thehosts 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

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

found in uveal tissue. Post-traumatic uveitis and orchiditis after vasectomy may fall in this category. Molecular Mimicry. It is imposible that certain autoimmune disorders are caused by molecular mimicry, in which a foreign antigen so closely resembles a self antigen that antibodies produced against the former react with the latter. A humoral or cellular response can be mounted against antigenically altered or injured tissue, creating an immune process. In rheumatic fever and acute glomerulonephritis, for example, a protein in the cell wall group A B-hemolytic streptococci has considerable similarity with antigens in heart and kidney tissue, respectively. After infection, antibodies directed against the microorganism cause a classic case of mistaken identity, which leads to inflammation of the heart or kidney. Certain drugs, when bound to host proteins or glycoproteins, from a complex to which a humoral response is directed with substantial cross reactivity to the original self protein. The antihypertensive agent methyldopa can bind to surface antigens on red cells to induce an antibody-mediated hemolytic anemia. Not everyone exposed to group A B-hemolytic streptococci has an autoimmune reaction. 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. The HLA type determines exactly which fragments of a pathogen are displayed on the cell surface for presentation to T cells. One individuals HLA may bind self-mimicry molecules for presentation to T cells, and anothers HLA type may not. In the spondyloarthritis, there is a clear relationship between arthritis and a prior bacterial infection, combined with the inherited HLA-B27 antigens. Superantigens. Superantigens are a family of related substances, including staphylococcal and streptococcal exotoxins, which can short-circuit the normal sequence of events in an immune response, leading to inappropriate activation of CD4+ helper T cells. Superantigens do not require processing and presentation of antigen by APCs to induce a T-cell response. Instead, they are able to interact with a TCR outside the normal antigen-binding site. Normally, only a small percentage of the T-cell population (0.01%) is stimulated by the presence of proecesed antigens on the surface of macrophages; however, superantigens can interact with 5% to 30% of T cells. Superantigens directly link the class II MCH complex molecules of APCs such as macrophages to TCRs, causing a massive release of T-cell inflammatory cytokines, primarily IL2 and tumor necrosis factor- (TNF ), and an uncontrolled proliferation of T cells. At least one disease in adults, toxic shock syndrome, ismediated by superantigens. Kawasaki disease in children probably has a similar cause. Heredity and Gender Genetic factors can increase the incidence and severity of autoimmune diseases, 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. For example, 90% of persons with ankylosing spondylitis carry the HLA B27 antigen,as compared with 7% of persons without the disease. Other HLAassociated diseases are Reiters syndrome and HLA-B27, rheumatoid arthritis and HLA-DR4, and systemic lupus erythematosus (SLE) and HLA-DR3. The molecular basis for these associations is unknown. Because autoimmunity does not develop in all persons with genetic predisposition, it appears that other factors, such as a trigger event, interact to precipitate the altered immune state. The event or events that trigger the development of an autoimmune response are unknown. It has been suggested that the trigger may be a virus or other microorganism, a chemical substance, or a self antigen from a body tissue has been hidden from the immune system during development. A number of autoimmune diseases such as SLE occur more commonly in women than men, suggesting that estrogens may play a role in the development of autoimmune disease. Evidence suggests that estrogens stimulate and androgens suppress the immune response. For example, estrogen stimulates a DNA sequence that promotes the production of interferon , which is thought to assist in the induction of n autoimmune response. Diagnosis and Treatment of Autoimmune Disease Suggested criteria for determining that a disorder is an autoimmune disorder include evidence of an autoimmune reaction, determination that the immunologic findings are not secondary to another condition, and the lack of other identified causes for the disorder. Currently, the diagnosis of autoimmune disease is based primarily on clinical findings and serologic testing. In the future, it is likely that autoimmune disorders will be diagnosed by directly identifying the genes responsible for the condition. The basis for most serologic assays is demonstration of antibodies directed against tissue antigens or cellular components. For example, a child with chronic or acute history of fever, arthritis, and a macular rash along with high levels of antinuclear antibody has a probable

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

pointing to important roles of interferon alpha, transcription factors, and signaling variations also point to a central role for neutrophils Etiology Although the specific cause of SLE is unknown, multiple genetic predispositions and geneenvironment interactions have been identified (see chart below). This complex situation perhaps explains the variable clinical manifestations in persons with SLE. Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations. At least 35 genes are known to increase the risk of SLE. A genetic predisposition is supported by the 40% concordance among monozygotic twins. If a mother has SLE, her daughter's risk of developing the disease has been estimated at 1:40 and her son's risk is 1:250. Studies of human leukocyte antigens (HLA) reveal that HLA-A1, B8, and DR3 are more common in persons with SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement (especially C4, C2, and other early components) are also associated with an increased risk of SLE. Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity. Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses, including to protein regions homologous to nuclear antigens. Viruses may stimulate specific cells in the immune network. Chronic infections may induce anti-DNA antibodies or even lupuslike symptoms, and acute lupus flares often follow bacterial infections. Environmental and exposure-related causes of SLE are less clear. Silica dust and cigarette smoking may increase the risk of developing SLE. Administration of estrogen to postmenopausal women appears to increase the risk of developing SLE. Breastfeeding is associated with a decreased risk of developing SLE. Photosensitivity is clearly a precipitant of skin disease. 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. Epidemiology United States statistics In the United States, the annual incidence of SLE averages 5.1 per 100,000 population. The reported prevalence is 52 cases per 100,000 population. According to a 2008 report from the National Arthritis Data Working Group, approximately 250,000 Americans have SLE. The frequency of SLE could be increasing due to milder forms of the disease that are now being recognized. The frequency of SLE varies by race and ethnicity, with higher rates reported among black and Hispanic people. The prevalence of SLE is approximately 40 per 100,000 whites in Rochester, Minnesota, versus 100 per 100,000 Hispanic persons in Nogales, Arizona. The incidence of SLE in black women is approximately 4 times higher than in white women. SLE is also more frequent in Asian women than in white women. International statistics Worldwide, the prevalence of SLE varies. The highest prevalences have been reported in Italy, Spain, Martinique, and the United Kingdom Afro-Caribbean population. Although the prevalence of SLE is high in black persons in the United Kingdom, the disease is rarely reported among blacks who live in Africa, suggesting that there may be an environmental trigger as well as a genetic basis for their disease. Race-, sex-, and age-related demographics Worldwide, the prevalence of SLE appears to vary by race. However, different prevalence rates occur among people of the same race in different geographical locations. 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. In general, black women have a higher rate of SLE than any other race, followed by Asians, then white women. In the United States, black women are 4 times more likely to have SLE than white women. SLE frequently starts in women of childbearing age, and the use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease. The risk of SLE development in men is similar to that in prepubertal or postmenopausal women. Interestingly, SLE is more common in men with

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

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

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. 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. 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, medical facilities are sometimes poorly equipped and tests to measure CD4 count and viral load are unavailable. 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, which may be used to guide medical decision making. 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, tonsillitis, otitis media, 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

Pulmonary tuberculosis Severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Unexplained* anaemia (below 8 g/dl), neutropenia (below 0.5 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, genital or anorectal of more than one months duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, 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, 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, Diagnosis, and Treatment Because there is no cure for HIV or AIDS, adopting a risk free or low risk behavior is the best protection against the disease. Abstinence or long term, mutually monogamous sexual relationships between two uninfected partners are the best way to avoid HIV infection and other STDs. 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. 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 most accurate and inexpensive method for identifying HIV is the HIV antibody test. The HIV antibody test procedure consists of screening with an enzyme immunoassay (EIA), also known as enzymelinked immunosorbent assay (ELISA), followed by a confirmatory test, the Western blot assay which is performed if the EIA is positive. EIA tests are used first because they are less expensive and are quicker to perform. The EIA detects antibodies produced in response to HIV infection. In an EIA test, when blood is added, antibodies to HIV bind to HIV antigens. The antigen antibody complex is then detected using an antihuman immunoglobulin G (IgG) antibody conjugated to an enzyme like alkaline phosphatase. A substrate is then added from which the enzyme produces a color reaction. Color development, indicating the amount of HIV antibodies found, is measured. The test is considered reactive, or positive, if color is produced, and negative, or non reactive, if there is no color. EIA tests high false-positive rates; thus samples that are repeatedly reactive are tested by a confirmatory test such as Western blot. The Western blot is more sensitive assay that looks for presence of antibodies to specific viral antigens. When a serum antibody test result is reactive or borderline by EIA and positive by Western blot,the person is considered to be infected by HIV. When EIA is reactive, and the Western blot is negative, the person is not infected with HIV. Both tests areimportant because in someinstitution, 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. The Western blot test therefore is essential to determine which persons withn positive EIA tests are truly infected.

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

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