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T-cells activation Immune response-regulation Cell mediated immune responses Antigen-specific cell –mediated responses are carried out by Tlymphocyte .T cells can lyse cells expressing specific antigens(Cytotoxicity) or release cytokines which trigger inflammation (delayed hypersensitivity). These two types of T-cell response are mediated by distinct populations , Cytotoxicity is the role of cytotoxic T (Tc) cells and delayed hypersensitivity that of helper T cells. These two types of T cells are responsible for combating intracellular pathogens (all viruses, certain bacteria and parasites) which are inaccessible to antibodies and drug. Cytotoxic T cells lyse cells infected with virus. Such Cytotoxicity is virus specific and only cells expressing the relevant viral proteins on their surface are killed . Since infected cells express surface viral proteins prior to the assembly of new virus particles and viral budding, Cytotoxic T cells are important in the recovery phase of an infection, destroying the infected cells before new virus particles are generated. In contrast to helper T cells ,Cytotoxic T cells recognize viral antigens together with MHC class 1 molecules .They show exquisite specificity for self MHC antigens in that they can only lyse cells expressing the same MHC class 1 molecules. Delayed-type hypersensitivity(DTH) reactions are mediated by specific T-cells which produce TH1 type cytokines on exposure to antigen. The tuberculin test (Mantous test) is agood example of a DTH response. Individuals who have previously been infected with Mycobacterium tuberculosis mount a T cell response which evolves over 24-72 h following intradermal injection of tuberculin . This is clinically manifest as local swelling and induration, biopsy of tissue granulomas in tuberculosis and sarcoidosis are further examples of DTH . Like the induction of T cell help, the induction of delayed hypersensitivity may also be subject to MHC polymorphism T- LYMPHOCYTES activation: T lymphocytes also arise in the bone marrow. Unlike B cells, which mature within the bone marrow, T cells migrate to the thymus gland to mature. During its maturation within the thymus, the T cell comes to express a unique antigen-binding molecule, called the T-cell receptor, on its membrane. Unlike membrane-bound antibodies on B cells, which can recognize antigen alone, T-cell receptors can recognize only antigen that is bound to cellmembrane proteins called major histocompatibility complex (MHC) molecules. MHC molecules that function in this recognition event, which is termed “antigen presentation,” are polymorphic (genetically diverse) glycoproteins found on cell membranes. There are two major types of MHC molecules: Class I MHC molecules, which are expressed by nearly all nucleated cells of vertebrate species, consist of a heavy chain linked to a small invariant protein called _2-microglobulin. Class II MHC molecules, which consist of an alpha and a beta glycoprotein chain, are expressed only by antigen-presenting cells. When a Naive T cell encounters antigen combined with a MHC molecule on a cell, the T cell proliferates and differentiates into memory T cells and various effector T cells. There are two well-defined subpopulations of T cells: T helper (TH) and T cytotoxic (TC) cells. Although a third type of T cell, called a T suppressor (TS) cell, has been postulated, recent evidence suggests that it may not be distinct from TH and TC subpopulations. T helper and T cytotoxic cells can be distinguished from one another by the presence of either CD4 or CD8 membrane glycoproteins on their surfaces. T cells displaying CD4 generally function as TH cells, whereas those displaying CD8 generally function as TC cells. After a TH cell recognizes and interacts with an antigen–MHC class II molecule complex, the cell is activated—it becomes an effector cell that secretes various growth factors known collectively as cytokines. The secreted cytokines play an important role in activating B cells , cells, macrophages, and various other cells that participate in the immune response. Differences in the pattern of cytokines produced by activated TH cells result in different types of immune response. Under the influence of TH-derived cytokines, a TC cell that recognizes an antigen–MHC class I molecule complex proliferates and differentiates into an effector cell called a cytotoxic T lymphocyte (CTL). In contrast to the TC cell, the CTL generally does not secrete many cytokines and instead exhibits cell-killing or cytotoxic activity. The CTL has a vital function in monitoring the cells of the body and eliminating any that display antigen, such as virus-infected cells, tumor cells, intracellular bacteria, and cells of a foreign tissue graft. Cells that display foreign antigen complexed with a class I MHC molecule are called altered self-cells; these are targets of CTLs. ANTIGEN-PRESENTING CELLS Activation of both the humoral and cell-mediated branches of the immune system requires cytokines produced by TH cells. It is essential that activation of TH cells themselves be carefully regulated, because an inappropriate T-cell response to selfcomponents can have fatal autoimmune consequences. To ensure carefully regulated activation of TH cells, they can recognize only antigen that is displayed together with class MHC II molecules on the surface of antigen-presenting cells (APCs). These specialized cells, which include macrophages, B lymphocytes, and dendritic cells, are distinguished by two properties: (1) They express class II MHC molecules on their membranes. (2) They are able to deliver a co-stimulatory signal that is necessary for TH-cell activation. Antigen-presenting cells first internalize antigen, either by phagocytosis or by endocytosis and pinocytosis , and then display a part of that antigen on their membrane bound to a class II MHC molecule. The TH cell recognizes and interacts with the distinctive membrane molecules on lymphocytes. (a) B cells have about 100 000 molecules of membrane-bound antibody per cell. All the antibody molecules on a given B cell have the same antigenic Specificity and can interact directly with antigen. (b) T cells bearing CD4 (CD4+ cells) recognize only antigen bound to class II MHC molecules. (c) T cells bearing CD8 (CD8+ cells) recognize only antigen associated with class I MHC molecules. In general, CD4+cells act as helper cells and CD8+ cells act as cytotoxic cells. Both types of T cells express about 100 000 identical molecules of the antigen binding Tcell receptor (TCR) per cell, all with the same antigenic specificity. Pulmonary TB Pulmonary TB may manifest itself in several forms endobronchial TB with focal lymphadenopathy progressive pulmonary disease pleural involvement reactivated pulmonary disease Symptoms of primary pulmonary disease in the pediatric population often are meager Fever, night sweats, anorexia, nonproductive cough, failure to thrive, and difficulty gaining weight may occur Extrapulmonary TB Extrapulmonary TB includes peripheral lymphadenopathy, tubercular meningitis, miliary TB, skeletal TB, and other organ involvement. Congenital TB Congenital TB is a rare entity. Symptoms typically develop during the second or third week of life poor feeding poor weight gain cough lethargy irritability Other possible symptoms include fever, ear discharge, and skin lesions Congenital TB the infant should have proven TB lesions and at least one of the following: Lesions in the first week of life Documentation of TB infection of the placenta or the maternal genital tract Presence of a primary complex in the liver Exclusion of the possibility of postnatal transmission TB Disease Defects in cell-mediated immunity HIV Steroid therapy, cancer chemotherapy, and hematologic malignancies increase the risk of TB Malnutrition Non-TB infections, such as measles, varicella, and pertussis, Lab Studies the diagnosis of TB in children is extremely challenging because of difficulty in isolating M tuberculosis initial step is to obtain appropriate specimens for bacteriologic examination Gastric aspirates are used in lieu of sputum in very young children (<6 y) An early morning sample should be obtained, before the child has had a chance to eat or ambulate, as these activities dilute the bronchial secretions accumulated during the night Regulation of the immune response The specific immune involving activation and clonal expansion of B cells brings into play a variety of nonspecific effector mechanisms involving complement, cytokines, granulocytes, macrophages, mast cells etc. These have the potential to damage normal host tissues ,so it is crucial that the specific immune response be swiftly curtailed once the initiating foreign invader has been effectively neutralized. • Anti-idiotypic antibody Variable regions, or idiotypes (ids),of antibodies ,BCRs and TCRs represent novel molecules not previously experienced by the immune system. Tolerance will not have been induced against them and ,if present in sufficient quantity, as occurs during a clonally expanded immune response, they will be immunogenic and induce anti-idiotypic antibodies(ant-ids). Secreted antibody may be recognized by B cells bearing BCRs with anti-id reactivity. This usually takes place on the surface of follicular dendritic cells and transmits activation signal 1 to the anti-id B cell. The fully activated anti-idiotypic B cell undergoes clonal expansion and secretes anti-id .This will form immune complex with circulation id which will be removed by phagocytes. Anti-id will also bind to id (BCR) on the surface of B cells. This will lead to cross –linking of FcRs,which generates an inactivation signal. The TCR on clonally expanded activated T cells can also lead to the generation of anti-id, which could induce tolerogenic signals when it binds to cell-bound TCR, perhaps by inducing activation signal 1 in the absence of signal 2. • T suppressor cells Activation of immune effector mechanisms involving B cells ,cytotoxic T cells,Macrophages or NK cells all require participation of T helper cells and their secreted lymphokines . Termination of a successful immune response could the driving T helper cells. The phenomenon of T helper inactivation by T suppressor cells has been difficult to prove, and although most immunologists now accept the existence of this specialized T-cell subset ,its mode of action is still unclear . As T helper cells recycle their TCRs and process TCR id peptides on to MHC-1,CD8 T cells with appropriate ant-id TCRs might bind to and inactivate the T helper cell by cytotoxic mechanism or by transmitting ،off signals ، through membrane interactions. 3-Cytokines An important mechanism of immune suppression is induction of a different cytokine profile from the one driving the ongoing reaction,e.g.suppression of cellmediated immunity by type 2 cytokines or suppression of humoral immunity by type 1 cytokines (immune deviation). A population of T regulatory cells that secrete mainly TGFB and or IL-10 also suppresses cytokinedepende immune reactions. Antigen Nature: polysaccharide antigens tend to elicit a predominant IgM+IgG2 response in contrast to protein antigens which elicite both cellular and humoral response. Dose: in experimental animals large doses of antigen induce tolerance. Route of administration: polio vaccine administered orally elicited a stronger antibody response than intramuscular injection. Antibody passive administration of antibody can be used to modulate immune response, e.g. maternal administration of antibodies to the red cell Rh antigen is used to prevent hemolytic disease of the newborn by removing fetal red cells from the maternal circulation. TST Induration of 10 mm or more is considered positive: Children who are at a higher risk of dissemination of tuberculous disease younger than 5 years immunosuppressed diabetes mellitus malnutrition those who were born in or whose parents were born in high-prevalence areas of the world those with travel histories to high-prevalence areas of the world TST Induration of 15 mm or more is considered a positive TST result in children aged 5 years or older without any risk factors for the disease TST False-positive reactions often are attributed to asymptomatic infection by environmental nontuberculous mycobacteria (due to cross-reactivity) TST False-negative results may be due to vaccination with live-attenuated virus, immunosuppression, immune deficiency, malnutrition. subcutaneous injection injection of too little antigen improper storage PPD has been recognized to have an initial false-negative rate of 29% Treatment The ultimate goal of treatment is to achieve sterilization of the TB lesion in the shortest possible time the regimens for the treatment of TB always should consist of multiple drugs. directly observed therapy (DOT) is recommended for treatment of TB MDR Outpatient Care Public health authorities should be notified of all cases of TB DOT is mandatory for the treatment of patients with coexistent HIV disease, those with MDRTB, and those who may be noncompliant. A regular follow-up appointment every 4-8 weeks should be scheduled to ensure compliance and to monitor the adverse effects of and response to the medications administered Outpatient Care Monitoring of liver function test miliary TB, tubercular meningitis, coexistence of other hepatic disorders with concomitant hepatotoxic drug therapy Outpatient Care Follow-up CXR may be obtained after 2-3 months of therapy to observe the response to treatment in patients with pulmonary TB. However, hilar lymphadenopathy may take several years to resolve. Thus, a normal CXR is not required for termination of therapy Prevention o The risk of acquisition of TB is particularly high in very young children (<5 y) and in the adolescent population. Thus, patients in these age groups with a positive TST result and no other manifestations should receive INH therapy. Active TB should be excluded carefully prior to the initiation of preventive therapy. Prevention For recent contacts of patients with contagious TB (ie, in the past 3 mo), INH therapy is indicated even if the TST result is negative. This is especially true for contacts who are infected with HIV or for household contacts younger than 5 years. Prevention The recommendations of the AAP are to administer 9 months of preventive therapy. The drug of choice is INH. A period of treatment of 12 months is recommended for patients with HIV infection. For the management of contacts of INHresistant cases, rifampin is recommended for 6 months in children Vaccination BCG is a live vaccine prepared from attenuated strains of M bovis Although BCG vaccine has been in use since 1921 and approximately 3 billion doses have been administered, its efficacy continues to be debated Vaccination Vaccine is efficacious against miliary and meningeal TB. Controversy exists about the efficacy of BCG against pulmonary TB The major role of BCG is the prevention of serious and life-threatening disease such as disseminated TB and tubercular meningitis in children. BCG vaccine does not prevent infection with M tuberculosis Vaccination From birth to age 2 months, administration of BCG does not require a prior TST. Thereafter, a TST is mandatory prior to vaccination Vaccination Adverse reactions due to the vaccine include subcutaneous abscess formation and the development of lymphadenopathy. Rare complications, such as osteitis of the epiphyses of the long bones and disseminated TB, may necessitate administration of antitubercular therapy, except for pyrazinamide Vaccination Contraindications immunosuppressed conditions Steroid HIV infection. However, in areas of the world where the risk of TB is high, the WHO recommends using the BCG vaccine in children who have asymptomatic HIV infection Thank you