lmmunology Community

Rheumatic Fever

Rheumatic Fever

“Innate immunity of the lungs in homeostasis and disease” read the review. Pdf

http://books.ms/main/5B6F1C71D9FF018CE4354BB37E30207F https://telegram.me/joinchat/AAAAAEGF1HigCuVnbybPZw

Pediatric Clinical Immunology and Rheumatology Rakesh Monda : 2024

Clinical Immunology. Principles and Practice Robert R. Rich, Elsevier: 2023

Immunodeficiencies Section II @immunology_community.

Immunodeficiency Section I @immunology_community

Continue: Human immunodeficiency virus 1 and 2 ========================= • In the acute seroconversion illness, there is a sharp fall in absolute CD4+ T-cell numbers and an increase in CD8+ T-cell numbers with T-cell activation markers increased (IL-2 receptor (CD25) and MHC class II (DR)); this normally returns rapidly to normal as evidence of viral replication disappears. Persistent CD4+ T-cell lymphopenia after seroconversion illness is a poor prognostic sign indicating rapid progression to terminal illness. • Sequential monitoring of the CD4+ T-cell numbers provides guidance on the rate of progression of disease and identifies levels at which therapeutic interventions may be indicated (e.g. Pneumocystis prophylaxis at 0.2×109/L CD4+ T cells). • Once the CD4+ T-cell count falls below 0.05×109/L, further monitoring is of little clinical value (except psychologically to patients, who view cessation of monitoring as doctors giving up). • Successful treatment with HAART will lead to a rise of CD4+ T cells to within the normal range and suppression of viral load. • Immune function will recover in patients with a good response to HAART: • rapid increase in CD4 recovery is biphasic • + T cells in fi rst 3–6 months, mainly CD45RO+ memory T cells (decreased apoptosis and redistribution?) second phase is due to slower increase in CD54RA • +CD62L+ naive T cells owing to increased thymic emigration rapid increase in CD8 • • + T cells initially followed by decline return of cutaneous reactivity to recall antigens. • Serum immunoglobulins are usually polyclonally elevated (IgG levels >50g/L may be recorded); serial measurements have no clinical utility. Most of the antibody is either ‘junk’ or relates to an anamnestic response. • Autoantibodies may be detected (including antinuclear and dsDNA antibodies, anti-neutrophil cytoplasmic antibody (ANCA), and anti-cardiolipin). The presence of autoantibodies may cause serious diagnostic confusion, especially if the clinical presentation is atypical. • Rare patients, usually children, may suffer from panhypo- gammaglobulinaemia or specific antibody deficiency, presenting with recurrent bacterial infections; these patients may derive significant benefit from IVIg. It has been more difficult to demonstrate specific antibody defects in adults, although a subpopulation of adult patients do have recurrent sinopulmonary infections with Haemophilus and Pneumococcus: IVIg seems to be less helpful. • Serum B2-microglobulin levels may be elevated, as a marker of increased lymphocyte turnover; however, the range of elevation in HIV+ patients is small compared with that seen in lymphoproliferative disease, and its value (except where CD4+ T-cell counts are unavailable) is small. Serum and urinary neopterin, a marker of macrophage activation, may also be elevated. There is little to choose between these two surrogate markers and viral load is much more clinically relevant. Immunotherapy • The mainstay of therapy at present is the use of antiretroviral agents. Mono- or dual-agent therapy is not recommended. Complex multi-agent regimes are now used. The reader is advised to consult the current HIV literature for information on the current state of therapeutic options. Some regimes require strict timing of administration and high levels of compliance. Multiresistant HIV strains have been reported. • IVIg may be helpful in certain HIV+ infants, although not in adults. • Other immunotherapies (interferons, IL-2) have been uniformly disappointing and are not used routinely. A-IFN enjoyed a vogue in the treatment of Kaposi’s sarcoma (due to HHV-8), but the latter responds better to cytotoxic therapy and radiation. • Use of passive immunotherapy has been disappointing. https://telegram.me/joinchat/AAAAAEGF1HigCuVnbybPZw

• In the acute seroconversion illness, there is a sharp fall in absolute CD4+ T-cell numbers and an increase in CD8+ T-cell numbers with T-cell activation markers increased (IL-2 receptor (CD25) and MHC class II (DR)); this normally returns rapidly to normal as evidence of viral replication disappears. Persistent CD4+ T-cell lymphopenia after seroconversion illness is a poor prognostic sign indicating rapid progression to terminal illness. • Sequential monitoring of the CD4+ T-cell numbers provides guidance on the rate of progression of disease and identifies levels at which therapeutic interventions may be indicated (e.g. Pneumocystis prophylaxis at 0.2×109/L CD4+ T cells). • Once the CD4+ T-cell count falls below 0.05×109/L, further monitoring is of little clinical value (except psychologically to patients, who view cessation of monitoring as doctors giving up). https://telegram.me/joinchat/AAAAAEGF1HigCuVnbybPZw

📌Human immunodeficiency virus 1 and 2📌 ========================== HIV-1 and HIV-2 are retroviruses, responsible for the acquired immuno deficiency syndrome (AIDS). Immunological features: --------------------- • Virus enters the cells via a cognate interaction of the gp120 env with CD4 and a chemokine receptor, either CxCR4 or CCR5. • It also infects other CD4+ cells (macrophages, dendritic cells) and other cells expressing CD4-like surface proteins (neuronal cells). • Macrophage tropic viruses use CCR5, and infect T cells poorly; T-cell tropic viruses use CXCR4 for entry and form syncytia. • Resistance to viral infection is associated with polymorphism in the chemokine receptors. • A viral isolate entering T cells via CD8 has been described. • Uptake of virus into phagocytic cells may be augmented by antibody, and complement. HIV activates complement. • High levels of viral replication may take place in lymph nodes. • Initial viraemia after infection is controlled by CD8+ cytotoxic T cells (increased cell numbers). The asymptomatic phase is characterized by strong cytotoxic responses, but viral replication still detectable intermittently, i.e. HIV is not a true latent virus. • The antibody response to major viral proteins appears after a lag phase of up to 3 months and persists through the asymptomatic phase but declines in late-stage disease. • Marked B-cell dysfunction with polyclonal increase in immunoglobulins and the appearance of multiple autoantibodies. • In the seroconversion illness there is a dramatic fall in CD4+ T cells and rise of CD8+ T cells. The levels of CD4+ T cells may drop to a level at which opportunistic infections may occur at this early stage (poor prognostic indicator). Levels then usually recover to within the low normal range. There is then a slow decline of absolute CD4+ T-cell count over time (years) following infection. • Passage to the symptomatic phase is characterized by a rapid drop in CD4+ T cells, loss of cytotoxic activity, and switch of virus type from slow-growing, non-syncytial-forming strains to rapidly growing, syncytial-forming strains (quasi-species evolving through lack of replicative fidelity and under immunological selection pressure). This is accompanied by the occurrence of opportunistic infections. • Activation of T cells enhances viral replication and hence CD4+ T-cell destruction. Therefore opportunistic infections enhance the self- destruction of the immune system. Long-term non-progressors and • patients responding to highly active antiretroviral therapy (HAART) show good proliferative responses to gag proteins. Progression has been associated with a switch from Th1 to Th2 responses. • HIV preferentially infects CD45RO+ cells but the depletion of T cells principally affects CD45RA+CD62L+ naive T cells. • T-cell depletion is caused by increased apoptosis, impaired production (HIV effects on thymus), and destruction of both infected and uninfected cells. • HIV replication is suppressed by natural CCR5 chemokine ligands, RANTES, MIP-1A, and MIP-1B, which are secreted by CD8+ T cells. SDF-1A is the natural ligand for CXCR4. High levels of chemokine production have been associated with resistance to infection. Diagnosis and monitoring ---------------------- • Diagnosis depends on the detection of antiviral antibody ± viral antigen, not on immunological markers. Screening tests for anti-HIV antibody are followed up by PCR-based tests. Informed consent must be obtained. • The most accurate monitoring of disease is now available through measurements of viral load by quantitative PCR (viral load). 0 Lymphocyte surface markers (CD4 count) must not be used as a way of HIV testing without consent. • CD4+ T cell numbers will be reduced and CD8+ T cells increased in most acute viral infections and in seriously ill patients in the ITU setting. https://telegram.me/joinchat/AAAAAEGF1HigCuVnbybPZw

📌Chronic GvHD (cGvHD)📌 ===================== • cGvHD is the most common non-relapse problem post-allogeneic transplantation. • Risk factors for cGvHD are: aGvHD (most important) • increasing age • donor–recipient gender mismatch • • MHC mismatch • lack of T-cell depletion. • Disease may evolve: • following a period of resolution (‘interrupted’) directly from aGvHD (‘progressive’) • de novo • in patients with no history of aGvHD. • De novo form has a good prognosis. • Progressive form has a grim prognosis. • Interrupted form has an intermediate prognosis. • cGvHD has many features in common with systemic sclerosis and collagen vascular disorders. • Features occurring most commonly are: • liver (raised bilirubin, transaminases, and ALP) skin (lichen planus, pigmentation, scleroderma) • • mouth (lichen planus, xerostomia, ulcers) • eyes (keratoconjunctivitis sicca, corneal ulcerations). • Any organ may be affected. • Complications: • and malabsorption gastrointestinal involvement results in fibrosis, abnormal motility, • • bronchiectasis lung involvement may cause bronchiolitis obliterans and infection is the major cause of mortality. • Dysregulation of the immune system and cGvHD therapy lead to severe immunosuppression. • Dysregulation leads to: autoantibody formation • hypo- or hypergammaglobulinaemia • CD8 • + T-cell numbers are usually markedly increased. • Steroids, mycophenolate mofetil, tacrolimus, and ciclosporin are used for first-line treatment. • Second-line therapies include thalidomide, azathioprine, and monoclonal antibody therapy. • Response rates to treatment are generally poor. • Untreated, all patients will die. https://telegram.me/joinchat/AAAAAEGF1HigCuVnbybPZw

Graft-versus-host disease (GvHD) ☆☆☆☆☆☆☆☆☆☆☆☆☆ • GvHD occurs when transplanted immunocompetent donor T cells recognize HLA mismatch and initiate an immune response. • The major risk factor for development of GvHD is MHC disparity between donor and recipient. • GvHD may occur, despite good matching by molecular techniques, because of: • • non-MHC-encoded gene polymorphisms differences in the minor histocompatibility antigens • cytokine polymorphisms. • A disease resembling GvHD may be seen in autologous transplants, possibly caused by the development of autoreactive T cells. ========================= 📌 Acute GvHD (aGvHD) ------------------- • Severe aGvHD is now rare owing to improved matching and better T-cell depletion, in combination with stem cell enrichment. • aGvHD is defined as occurring before an arbitrary 100-day period. • Classic chronic GvHD (cGvHD) may be present before day 100 Manifestations of aGvHD may occur after day 100 post-transplant. • and is better defined by clinical manifestations than timing. • Development of aGvHD is a cause of significant morbidity and mortality. • Infection occurs in aGvHD due to the immunosuppression used to Most deaths occur due to infection. • • treat it. aGvHD is itself immunosuppressive. • aGvHD causes damage mainly to rapidly dividing tissues, particularly affecting: skin • • liver • gut. • It is graded from I (mild) to IV (severe). • Skin is most commonly affected site with typical distribution of rash affecting palms and soles initially, progressing to face, head, and body. • Main sign of GI involvement is diarrhoea (may be profuse). • Hyperbilirubinaemia and raised ALP are seen with hepatic involvement. • Diagnosis is usually obvious clinically. • May be confirmed on biopsy, showing infiltrates of mature T cells with increased tissue MHC class II expression. • Donor T cells in graft are causative. • aGVHD may be reduced by T-cell depletion. • Tissue damage occurs due to direct cellular toxicity and high cytokine production (IL-1, TNFA, γ-IFN). • Reduced intensity conditioning and cord donors are associated with a decreased incidence of aGvHD. 📍 Prevention of aGvHD 📍 ------------------- • aGvHD prevention is attempted using immunosuppression and T-cell depletion. • Prophylactic T-cell suppression is achieved with combinations of methotrexate, ciclosporin, tacrolimus, and mycophenolate mofetil. • T-cell depletion is associated with higher engraftment failure and decreased graft-versus-tumour effect. 📍Treatment of aGvHD📍 --------------------- Treatment of established aGvHD is difficult. • First-line therapy is high-dose steroids. • Second-line therapy is anti-thymocyte globulin (ATG), Campath-1H, anti-CD25, and/or anti-TNF monoclonal antibodies. • Aggressive therapy early is important to prevent cGvHD. https://t.me/immunology_community