PATHO-A-IMMUNE-2-MEDTRANS2027.docx.pdf

PATHOLOGY A | DR. DARYL ALVIN REQUISO 1 AUTOIMMUNE DISORDERS RHEUMATOID ARTHRITIS In practice, these autoimmune diseases are overlapping, PATH...

PATHOLOGY A | DR. DARYL ALVIN REQUISO 1 AUTOIMMUNE DISORDERS RHEUMATOID ARTHRITIS In practice, these autoimmune diseases are overlapping, PATHOGENESIS AND CLINICAL MANIFESTATION very hard to distinguish from each other. PATHOGENESIS RHEUMATOID ARTHRITIS (RA) Chronic inflammatory disease a ecting joints, producing a nonsuppurative proliferative and inflammatory synovitis May also involve extra articular tissues ○ Skin, blood vessels, lungs, heart Autoimmune condition Often progresses to articular cartilage destruction and, in some cases, joint fusion (ankylosis). Autoimmune response in RA is initiated by CD4+ helper T cells The activated CD4+ T cells release inflammatory mediators that stimulate other inflammatory cells, leading to tissue injury RA is three times more common in women than in men. From Th1 cells, which activates macrophages IFN-γ and resident synovial cells. From Th17 cells that recruits neutrophils and IL-17 monocytes. Expressed on activated T cells and stimulates RANKL bone resorption. Macrophages stimulate resident synovial cells TNF and IL-1 to secrete proteases that destroy hyaline Some patients will be susceptible for development and cartilage. there will be failure of tolerance and unregulated lymphocyte activation → T and B cell responses to self antigens → Lymphocytes, antibodies and immune Synovium often contains germinal centers complexes enter the joint With secondary follicles and abundant plasma cells. ○ Fibroblasts, chondrocytes, and synovial cells are Some of these plasma cells secrete antibodies that activated → will proliferate and release cytokines recognize self antigens ○ All of these will act in unison to cause damage → Many of these autoantibodies, which are produced in leading to Pannus formation and Destruction of lymphoid organs as well as synovium, are specific for bone and cartilage citrullinated peptides (CCPs) in which arginine residues are post-translationally converted to citrulline. Anti-citrullinated peptide antibodies (ACPAs) are diagnostic markers that can be detected in serum of up to 70% of RA patients IgM and IgA autoantibodies that bind to IgG Fc regions are present in 80% of individual (Rheumatoid Factor) 50% of the risk of developing RA is related to inherited genetic susceptibility. The HLA-DR4 allele is associated with ACPA-positive RA In RA, there will be chronic inflammation, wherein will ○ Evidence suggests that an epitope on a citrullinated lead to Pannus formation. protein, vinculin, mimics an epitope on many ○ In chronic inflammation there is concomitant microbes and can be presented by the class II repair. There will be proliferation of cartilage and HLA-DR4 molecule. fibrous tissue. Environmental factors that promote autoimmunity are Pannus formation: consists of germinal involved (not clearly established) centers and lymphoid aggregates ○ Infection There is a tendency for joints to fuse → fused ○ Smoking joints become nonfunctional and hinder may promote citrullination of self proteins, movement of the joint if damage is severe and creating new epitopes that trigger progressive. autoantibody production. This may extend beyond the joints and may deposit as nodules (rheumatoid nodule) FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 2 SJOGREN SYNDROME (DRY EYES AND MOUTH) Characterized by the following: ○ Chronic disease ○ Dry eyes (keratoconjunctivitis sicca) ○ Dry mouth (xerostomia) Immunologically mediated destruction of the lacrimal and salivary gland The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen Rheumatoid Nodule - looks like a granuloma of TB; has expressed in these glands, or immune reactions against activated macrophages, necrotizing fibrinoid necrosis. the antigens of a virus that infects the tissues. ○ Resembles fibrin ○ May deposit at any parts of the body particularly in SJOGREN SYNDROME FORMS the subcutaneous area of the forearm PRIMARY FORM SECONDARY FORM ○ These small masses are firm, nontender, and round Also known as Sicca More often in association to oval. Microscopically, they resemble necrotizing Syndrome with another granulomas with a central zone of fibrinoid necrosis autoimmune disease surrounded by a prominent rim of activated ○ Most common macrophages and numerous lymphocytes and association is RA plasma cells. Other associated ○ Severe disease may be associated with conditions: SLE, leukocytoclastic vasculitis, an acute necrotizing polymyositis, vasculitis of small and large arteries that may scleroderma, vasculitis, involve pleura, pericardium, or lung and evolve into mixed connective tissue a chronic fibrosing process. Leukocytoclastic disease, or thyroiditis vasculitis produces purpura, cutaneous ulcers, and SJOGREN SYNDROME nail bed infarction. Ocular changes such as uveitis PATHOGENESIS & CLINICAL FEATURES and keratoconjunctivitis (similar to Sjögren Lymphocytic infiltration and fibrosis of the syndrome). lacrimal and salivary glands Red, edematous, painful, limitation in ○ CD4+ helper T cells and some B cells, movement due to ankylosis (fibrous or plasma cells bony ankylosis), eroded bones because ○ In chronic inflammation there is attempts of damage, eroded cartilages causes of repair forming fibrosis friction which contributes to pain. 75% of patients will have rheumatoid factor RA may be distinguished from other ANA is detected in around 50 to 80% of forms of polyarticular inflammatory patients by immunofluorescence assay. arthritis serologically by ACPA Antibodies directed against two detection and radiographically by ribonucleoproteins: SS-A (Ro) and SS-B (La) characteristic changes. P ○ Can be detected in as many as 90% of It begins with malaise, fatigue, and A patients by sensitive techniques. These generalized musculoskeletal pain in T CLINICAL antibodies are thus considered serologic about half of patients; joint H MANIFESTATION markers of the disease. These involvement develops after weeks to O autoantibodies are also present in a months. G smaller percentage of patients with SLE The pattern of joint involvement varies, E and hence are NOT entirely specific for but it is generally symmetrical and N Sjögren syndrome. a ects small joints before larger ones. E Aberrant T-cell and B-cell activation are both Symptoms usually develop in the hands S implicated and feet, followed in decreasing I Possible trigger (but not proven): Viral frequency by the wrists, ankles, elbows, S infection and knees. In the hands, the CD4+ T cells and B cells specific for these self metacarpophalangeal and proximal antigens may have escaped tolerance and are interphalangeal joints are involved, in able to react in genetically susceptible patients. contrast to OA. ○ The result is inflammation, tissue damage, and, eventually, fibrosis. However, the role of particular cytokines or T cell subsets in the development of the lesions is not established. ○ The nature of the autoantigens recognized by these lymphocytes is also mysterious. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 3 Sjögren syndrome–like disease is seen in Eventually the lymphocytic infiltrate becomes some patients with human T-lymphotropic extensive and lymphoid follicles with germinal virus (HTLV), human immunodeficiency centers may appear. The ductal lining epithelial virus (HIV), and hepatitis C virus cells may show hyperplasia, thus obstructing infections, but the link between these the ducts. viruses and the autoimmune disorder is Later there is atrophy of the acini, fibrosis, and obscure. hyalinization; still later in the course, atrophy and replacement of parenchyma with fat are seen. In some cases, the lymphoid infiltrate may be so intense as to give the appearance of a lymphoma. Indeed, these patients are at high risk for development of B-cell lymphomas. The lack of tears leads to drying of the corneal epithelium, which becomes inflamed, eroded, and ulcerated; the oral mucosa may atrophy, This is an example of a patient with Sjogren Syndrome, with inflammatory fissuring and ulceration; and there is enlargement of the salivary glands. dryness and crusting of the nose may lead to Biopsy: Lymphoid proliferation with tactile cell ulcerations and even perforation of the nasal hyperplasia septum. Target: Lacrimal and Salivary glands Sometimes other exocrine glands may be involved; SYSTEMIC SCLEROSIS respiratory tract, GI tract, or urogenital (vagina) (SCLERODERMA) ○ But these are extreme conditions Characterized by the following: Overtime, atrophy may happen within the acinar, as ○ Chronic inflammation thought to be the result of well as fibrosis, because of extensive inflammation, it autoimmunity will be highly fibrotic and the cells will be destroyed. ○ Widespread damage to small blood vessels, Mostly women between 50 to 60 years old ○ Progressive interstitial and perivascular fibrosis Keratoconjunctivitis produces blurring of in the skin and multiple organs (involves all vision, burning, and itching, and thick organs) secretions accumulate in the conjunc-tival sac. Mostly a ects skin (hence, scleroderma), but it goes Xerostomia results in di culty in swallowing beyond the skin. solid foods, a decrease in the ability to taste, ○ Although the term scleroderma is ingrained in C cracks and fissures in the mouth, and dryness clinical medicine, this disease is better named L of the buccal mucosa. systemic sclerosis because it is characterized by I excessive fibrosis throughout the body. Parotid Gland enlargement is present in N May a ect GI tract, kidneys, heart, muscles, lung one-half of patients. I Majority progresses to visceral involvement with death C Dryness of the nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis are other from renal failure, cardiac failure, pulmonary A L symptoms. insu ciency, or intestinal malabsorption. Extraglandular disease (⅓ of patients): F synovitis, di use pulmonary fibrosis, peripheral DIFFUSE SCLERODERMA LIMITED SCLERODERMA E neuropathy Widespread skin Often confined to A involvement at onset, fingers, forearms, and ○ More associated with high titers for SS-A T Rarely involves renal tubular function With rapid progression face. U Mikulicz syndrome and early visceral Visceral involvement R E ○ Combination of lacrimal and salivary involvement occurs late S gland inflammation was once called Clinical course is Mikulicz disease. relatively benign ○ Lacrimal and salivary gland enlargement CREST Syndrome from any cause, including sarcoidosis, (associated with IgG4-related disease, lymphoma, and Scleroderma) other tumors. ○ Calcinosis ○ Not specific for Sjogren Syndrome. ○ Raynaud M Lacrimal and salivary glands are the major phenomenon O targets of the disease, but other exocrine ○ Esophageal R dysmotility P glands, including those lining the respiratory H and gastrointestinal tracts and the vagina, may ○ Sclerodactyly O also be involved. The earliest histologic finding ○ Telangiectasia L in involved salivary glands is periductal and O perivascular lymphocytic infiltration. G y FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 4 PATHOGENESIS Telltale signs of endothelial activation and Autoimmune response injury (e.g., increased levels of von Vascular Damage Willebrand factor) and increased platelet Collagen Deposition activation (increased circulating platelet aggregates) have also been noted. However, what causes the vascular injury is not known; it could be the initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting damage on microvascular endothelium. Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger perivascular Not sure what is causing this condition fibrosis. Pathways: Widespread narrowing of the ○ T and B cell activation microvasculature leads to ischemic injury Which produces your antibodies, and more and scarring. importantly in this condition, it produces profibrotic Accumulation of alternatively activated cytokines (TGF-B, IL-13, Platelet-derived growth macrophages, actions of fibrogenic factor (PDGF)). cytokines produced by infiltrating These cytokines are inducing fibrosis, leading to the leukocytes, hyperresponsiveness of increase in synthesis of extracellular matrix protein fibroblasts to these cytokines, and scarring and fibrosis of the skin and parenchymal organs. following ischemic damage caused by the ○ Unknown external stimuli → endothelial injury → vascular lesions. FIBROSIS proliferation and obliterative vasculopathy → ischemia Fibroblasts from patients with systemic and repair of the organs, in a way it also leads to sclerosis have an intrinsic abnormality that fibrosis. causes them to produce excessive amounts And because there is obliterative vasculopathy, it of collagen. This idea is based on studies may lead to pulmonary arterial hypotension. with cultured fibroblasts, and whether or how this abnormality relates to CD4+ T cells responding to an as yet pathogenesis in vivo is unknown. unidentified antigen accumulate in the skin MORPHOLOGY and release cytokines that activate Majority of patients have di use, sclerotic atrophy of the inflammatory cells and fibroblasts. skin, Activated CD4+ T cells can be found in Usually begins in the fingers and distal regions of the A many patients, and Th2 cells have been upper extremities U isolated from the skin. Perivascular infiltrates containing CD4+ T cells and T TGF-β and IL-13, can stimulate the edema O transcription of genes encoding collagen With degeneration of collagen fibers I and other extracellular matrix proteins Capillaries and small arteries show thickening of the M (e.g., fibronectin) in fibroblasts. basal lamina, endothelial cell damage, and partial M There is also evidence for inappropriate occlusion U activation of humoral immunity, and the With progression of the disease, there is increasing N presence of various autoantibodies, fibrosis of the dermis I notably ANAs, provides diagnostic and T prognostic information. Y ○ Role of these ANAs in the pathogenesis of the disease is unclear; it has been postulated that some of these antibodies may stimulate fibrosis, but the evidence in support of this idea is not convincing. Microvascular disease - present early in the course of systemic sclerosis and may be the initial lesion. Scleroderma of the hands. Hands are sclerotic and thick. And VASCULAR Capillary dilation with leaking, as well as because there is a di use deposition of your collagen, and DAMAGE destruction, is also common. Nailfold fibrosis, there will be claw-like deformities capillary loops are distorted early in the course of disease, and later they disappear. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 5 specific for scleroderma If positive: More likely to have pulmonary fibrosis and peripheral vascular disease INFLAMMATORY MYOPATHIES In other words, inflamed muscles Inflammatory myopathies comprise an uncommon, heterogeneous group of disorders characterized by injury and inflammation of mainly the skeletal muscles Biopsy: normal (left); abnormal (right) that are probably immunologically mediated 1. Increase deposition of collagen 2. Fibrotic, 3. Presence of inflammation located at perivascular areas, MIXED CONNECTIVE TISSUE DISEASE 4. Relatively flat (top), Disease with clinical features that overlap with those of 5. Absent skin adnexa 1. SLE 2. Systemic sclerosis A ects 90% of patients 3. Polymyositis Progressive atrophy and collagenous fibrous High titers of antibodies to U1 ribonucleoprotein replacement of the muscularis may develop at Synovitis of the fingers, Raynaud phenomenon, myositis, any level of the gut and renal involvement GI TRACT Most severe in the esophagus. Disease may, over time, evolve into classic SLE or ○ Rubber-hose–like inflexibility systemic sclerosis ○ May lead to GERD and Barret Esophagus May cause malabsorption syndromes due to POLYARTERITIS NODOSA AND OTHER VASCULITIDES loss of villi and Microvilli Necrotizing inflammation of the walls of blood vessels Inflammation of synovium with synovial Strong evidence of immunologic mechanism MSK hypertrophy and hyperplasia. With fibrosis later General term noninfectious vasculitis di erentiates these ○ Some may develop inflammatory myositis conditions from those due to direct infection of the blood Occur in two-thirds of patients vessel wall ○ Interlobular arteries show intimal thickening as a result of deposition of mucinous or IgG-RELATED DISEASE finely collagenous material Constellation of disorders characterized by tissue ○ In hypertensive patients, vascular infiltrates dominated by IgG4 antibody–producing KIDNEYS alterations are more pronounced and are plasma cells and lymphocytes (particularly T cells), often associated with fibrinoid necrosis of fibrosis, obliterative phlebitis, and usually increased arterioles, thrombosis, and infarction serum IgG4. Such patients often die of renal failure, Described in virtually every organ system: pancreas, which overall accounts for about 50% the biliary tree, salivary glands, periorbital tissues, of deaths from systemic sclerosis. kidneys, lungs, lymph nodes, meninges, aorta, breast, Pulmonary involvement is seen in more than prostate, thyroid, pericardium, and skin 50% of individuals with systemic sclerosis and Many medical conditions long viewed as confined to LUNGS may manifest as interstitial fibrosis and single organs are part of the IgG4-RD spectrum pulmonary hypertension ○ Some forms of Mikulicz syndrome Pericarditis with e usion, myocardial fibrosis, ○ Riedel thyroiditis HEART and thickening of intramyocardial arterioles ○ idiopathic retroperitoneal fibrosis occur in one-third of patients. ○ Autoimmune pancreatitis CLINICAL MANIFESTATIONS ○ inflammatory pseudotumors of the orbit, lungs, Female-to-male ratio of 3 :1 and kidneys Peak incidence in the 50-60 year age group The pathogenesis of this condition is not understood, Distinctive features are the striking cutaneous changes, and although IgG4 production in lesions is a hallmark notably skin fibrosis of the disease Raynaud phenomenon, manifested as numbness and The key role of B cells is supported by initial clinical tingling of the fingers and toes caused by episodic trials in which depletion of B cells with anti–B cell vasoconstriction of arteries and arterioles reagents such as rituximab provided clinical benefit ○ Seen in virtually all patients and precedes other symptoms in 70% of cases Dysphagia – 50% of patients Abdominal pain, intestinal obstruction, malabsorption syndromes Ominous manifestation – malignant hypertension — suggestive of kidney damage Marker: DNA topoisomerase I (Anti-Scl 70) highly FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 6 PATTERNS AND MECHANISMS OF GRAFT REJECTION Graft rejection is classified into three: Hyperacute, Acute, and Chronic HYPERACUTE REJECTION Sensitized; incompatible Mediated by peformed antibodies can be a natural IgM antibodies specific for blood group antigens or antibodies specific for allogeneic MHC molecules induced prior exposure of the organ recipient through REJECTION IN TRANSPLANTATION blood transfusions, pregnancy or transplantation of MECHANISMS OF RECOGNITION AND REJECTION OF another organ ALLOGRAFTS Immediately after the graft is implanted and blood flow Rejection – T-lymphocytes and antibodies produced is restored, the antibodies bind to antigens on the graft against graft antigens react against and destroy tissue vascular endothelium and activate the complement grafts system, leading to endothelial injury, thrombosis, and Grafts exchanged between individuals of the same ischemic necrosis of the graft. species Rare - because every donor and recipient are matched ○ Allografts – same species for blood type, and potential recipients are tested for ○ Xenografts – another species antibodies against the cells of the prospective donor, a The major antigenic di erences between a donor and test called a cross-match. recipient that result in rejection of transplants are di erences in HLA alleles. ○ Highly polymorphic, there are always some di erences between individuals (except, of course, identical twins). RECOGNITION OF GRAFT ALLOANTIGENS BY T AND B LYMPHOCYTES Both lead to the activation of CD8+ T cells, which develop into CTLs, and CD4+ T cells, which become cytokine-producing e ector cells, mainly Th1 cells. The rejection response against solid organ transplants is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft: DIRECT INDIRECT presented to recipient T the graft antigens are cells by graft APCs picked up by host APCs, Most important for processed and presented MORPHOLOGY CTL-mediated acute to host T cells Gross Morphology: cyanotic, mottled, and anuric rejection Greater role in chronic Microscopic Morphology: platelet fibrin thrombi and rejection severe ischemic injury in a glomerulus (shown above); Both leads to development of activation of CD8+ T cells, exhibit acute fibrinoid necrosis of their walls and which develop into CTLs and CD4+ T cells, which become narrowing or complete occlusion of their lumens by cytokine-producing e ector cells, mainly Th1 cells. thrombi. DIRECT PATHWAY INDIRECT PATHWAY ○ Neutrophils rapidly accumulate within arterioles, Most important for the Play a greater role in glomeruli, and peritubular capillaries. cytotoxic chronic rejection ○ As these changes intensify and become di use, the lymphocyte-mediated glomerular capillaries also undergo thrombotic acute rejection occlusion, and eventually the kidney cortex The frequency of T cells that can recognize the foreign undergoes outright necrosis (infarction). A ected antigens in a graft is much higher than the frequency of kidneys are nonfunctional and have to be removed T cells specific for any microbe ACUTE REJECTION ○ Stronger immune response Mediated by T cells and antibodies activated by ○ May lead to rapid destruction of grafts alloantigens in the graft ○ Requires powerful immunosuppressive agents ○ Occurs within days or weeks after transplantation B lymphocytes also recognize antigens in the graft, ○ Principal cause of early graft failure including HLA and other antigens that di er between Two types: Acute cellular rejection & Acute cell-mediated donor and recipients rejection The activation of these B cells typically requires T cell ○ Acute Rejection - Acute Cellular Rejection help ○ Acute Antibody-mediated Rejection FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 7 Better prognosis Small vessels also may show focal CD8+ CTLs directly destroy graft cells thrombosis. Graft damage: CD4+ cells secrete cytokines and induce inflammation Endothelial damage: T cells react against graft vessels Immunosuppressive therapy: prevent and reduce acute reject by blocking the activation of alloreactive T cells MORPHOLOGY Two di erent patterns of injury: Tubulointerstitial pattern (type I) - there is extensive interstitial inflammation and tubular inflammation (tubulitis) associated with focal tubular (A) Graft damaged caused by antibody deposition in vessels injury. As might be expected, the (B) Light micrograph: inflammation in peritubular inflammatory infiltrates contain capillaries in a kidney graft activated CD4+ and CD8+ T lymphocytes. (C) Immunoperoxidase stain: CD4d deposition in glomerulus and peritubular capillaries Vascular pattern shows inflammation of vessels (type II) and sometimes necrosis CHRONIC REJECTION of vessel walls (type III). The a ected Indolent form of graft damage, occurs over months or A. ACUTE years, leading to progressive loss of graft function vessels have swollen endothelial cells, CELLULAR Manifests as interstitial fibrosis and gradual narrowing of and lym- phocytes are seen between the (T-CELL graft blood vessels (graft arteriosclerosis) endothelium and the vessel wall, a MEDIATED) finding termed endotheliitis or intimal REJECTION arteritis. The recognition of cellular rejection is important because, in the absence of accompanying humoral rejection, most patients respond well to immunosuppressive therapy. T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and (A): Destruction of graft cells by T cells activities of fibroblasts and vascular smooth muscle cells (B): Acute cellular rejection of kidney graft, with in the graft inflammatory cells in the interstitium and between epithelial Eventually narrows down and become occluded, then cells of the tubules (C): Rejection vasculitis in kidney graft, arteriole with coagulative necrosis of the parenchyma and atrophy of inflammatory cells attacking the endothelium tubules Poor prognosis Refractory to most therapies and becoming the principal Antibodies bind to vascular endothelium cause of graft failure and activate complement via the MORPHOLOGY classical pathway Dominated by vascular changes, often with intimal Graft failure: resultant inflammation and thickening and vascular occlusion. Chronically rejecting endothelial damage kidney grafts show glomerulopathy, with duplication of B. ACUTE MORPHOLOGY the basement membrane, likely secondary to chronic ANTIBODY - Manifested mainly by damage to endothelial injury, and peritubular capillaritis with MEDIATED glomeruli and small blood vessels. multilayering of peritubular capillary basement REJECTION Typically, there is inflammation of membranes. Interstitial fibrosis and tubular atrophy with glomeruli and peritubular capillaries, loss of renal parenchyma may occur secondary to the associated with deposition of vascular lesions. Interstitial mono- nuclear cell infiltrates complement products due to activation are typically sparse. of the complement system by the antibody-dependent classical pathway. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 8 SUMMARY TRANSPLANTATION OF HEMATOPOIETIC STEM CELLS Preformed antibodies bind to graft (HSCs) Hyperacute endothelium immediately after Use of HSC transplants to treat hematologic Rejection transplantation, leading to thrombosis, malignancies (ie. leukemia, lymphoma), bone marrow ischemic damage, and rapid graft failure. failure syndromes. T cells destroy graft parenchyma (and Historically, HSCs were obtained from the bone marrow, Acute Cellular but now they usually are harvested from peripheral vessels) by cytotoxicity and inflammatory Rejection blood after they are mobilized from the bone marrow by reactions. administration of hematopoietic growth factors, or from Acute Humoral Antibodies damage graft vasculature. the umbilical cord blood of newborn infants. Rejection ○ In most of the conditions in which HSC Dominated by arteriosclerosis, this type is Chronic Rejection transplantation is indicated, the recipient is caused by T-cell activation and antibodies irradiated or treated with high doses of Treatment of graft rejection relies on immunosuppressive chemotherapy to destroy the immune system (and drugs, which inhibit immune responses against the graft. sometimes, cancer cells) and to “open up” niches in Transplantation of HSCs requires careful matching of the microenvironment of the marrow that nurture donor and recipient and is often complicated by GVHD HSCs, thus allowing the transplanted HSCs to and immune deficiency. engraft. Problems inHSC transplantation: METHODS OF INCREASING GRAFT SURVIVAL ○ Graft-versus-host disease (GVHD) The value of HLA matching between donor and recipient Occurs when immunologically competent cells varies in di erent solid-organ transplants or their precursors are transplanted into ○ In kidney transplants, there is substantial benefit if immunologically compromised recipients, and all the polymorphic HLA alleles are matched the transferred cells recognize alloantigens in ○ HLA matching is usually not done for transplants of the host and attack host tissues liver, heart, and lungs, because other considerations It is seen most commonly in the setting of HSC Immunosuppressive therapy is essential in all transplantation but, rarely, may occur donor-recipient combinations following transplantation of solid organs rich in Immunosuppressive drugs in current use include steroids lymphoid cells (e.g., the liver) or transfusion of (which reduce inflammation), mycophenolate mofetil unirradiated blood. (which inhibits lymphocyte proliferation), and tacrolimus The immunocompetent T cells present in the (FK506). donor inoculum recognize the recipient’s HLA Tacrolimus, like its predecessor cyclosporine, is an antigens as foreign and react against them. inhibitor of the phosphatase calcineurin, which is To try to minimize GVHD, HSC transplants are required for activation of a transcription factor called done between donor and recipient who are nuclear factor of activated T cells (NFAT) HLA-matched using precise DNA NFAT stimulates transcription of cytokine genes, in sequencing–based methods for molecular particular the gene that encodes the growth factor IL-2. typing of HLA alleles. Tacrolimus inhibits T cell responses Plasmapheresis is used in cases of severe GRAFT-VERSUS-HOST DISEASE (GVHD) antibody-mediated rejection Days to weeks after allogeneic HSC transplantation. Type of blood donation machine that will Major clinical manifestations result from process the blood (ie. centrifuge) and collect involvement of the immune system and only the component needed and sends those epithelia of the skin, liver, and intestine APHERESIS Due CD8+ T cells plus considerable damage is that aren’t needed back to the donor; kind of ACUTE inflicted by cytokines released by the like a dialysis machine, but for blood GVHD sensitized donor T cells. donation Destruction of small bile ducts gives rise to Remove serum of the recipients, including jaundice, and mucosal ulceration of the gut THERAPEUTIC the antibodies present circulating the body, results in bloody diarrhea APHERESIS and replaced with albumin Considerable damage is inflicted by Although immunosuppression prolongs graft survival, it cytokines released by the sensitized donor T carries its own risks. cells One of the most frequent infectious complications is These patients have extensive cutaneous reactivation of polyoma virus. injury, with destruction of skin appendages CHRONIC ○ The virus establishes latent infection of epithelial and fibrosis of the dermis. GVHD cells in the lower genitourinary tract of healthy ○ Resembles systemic sclerosis individuals, and on immunosuppression, it is ○ Chronic liver disease - manifested by reactivated, infects renal tubules, and may even cholestatic jaundice is also frequent. cause graft failure. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 9 Depletion of donor T cells before transfusion virtually defective phagocyte function and eliminates the disease susceptibility to infections. How to eliminate T cells? The main leukocyte abnormalities are ○ Irradiation - blood unit (ie. stem cells) are exposed neutropenia (decreased numbers of neutrophils), defective degranulation, to radiation to eliminate T cells and maintain the and delayed microbial killing rest of the cells. Leukocytes contain giant granules, ○ HOWEVER: multifaceted T cells not only mediate which can be readily seen in peripheral GVHD but also are required for engraftment of the blood smears and are thought to result transplanted HSCs, suppression of EBV-infected from aberrant phagolysosome fusion. B-cell clones, and control of leukemia cells. In addition, there are abnormalities in melanocytes (leading to albinism), cells Immunodeficiency in HSC transplantation of the nervous system (associated with ○ Immunodeficiency may be a result of prior nerve defects), and platelets (causing treatment (e.g. leukemia) bleeding disorders) ○ Myeloablation The dysfunctional gene underlying this ○ Prior to HSC transplantation disorder encodes a cytosolic protein ○ A delay in repopulation of the recipient’s immune called LYST, which is believed to regulate system lysosomal tra cking. ○ Attack on the host’s immune cells by grafted INHERITED DEFECTS IN MICROBIAL ACTIVITY lymphocytes Decreased oxidative burst ○ Cytomegalovirus is particularly important ○ X-linked - Phagocyte oxidase Cytomegalovirus-induced pneumonitis can be (membrane component) a fatal complication. In one of the membrane-bound PRIMARY IMMUNODEFICIENCIES components (gp91phox) Genetically determined ○ Autosomal Recessive - Phagocyte Primary immunodeficiency diseases are caused by oxidase (cytoplasmic components) genetic (inherited) defects that a ect the defense Defects in the genes mechanisms: encoding two of the ○ Innate immunity (phagocytes, NK cells, or cytoplasmic components complement) (p47phox and p67phox) ○ The humoral and/or cellular arms of adaptive Chronic Characterized by defects in bacterial immunity (mediated by B and T lymphocytes Granulomatous killing that render patients susceptible to DEFECTS OF INNATE IMMUNITY disease recurrent bacterial infection Disease Defect CGD results from inherited defects in the DEFECTS IN LEUKOCYTE FUNCTION genes encoding components of INHERITED DEFECTS IN LEUKOCYTE FUNCTION phagocyte oxidase, the phagolysosomal Defective leukocyte adhesion because of enzyme that generates superoxide (O2) mutations in Beta chain of CD 11 / 18 The name of this disease comes from the Leukocyte macrophage-rich chronic integrins adhesion inflammatory reaction that tries to Have a defect in the biosynthesis of the deficiency 1 control the infection when the initial Beta 2 chain shared by the integrins LFA-1 and Mac-1 neutrophil defense is inadequate. This often leads to collections of Defective leukocyte adhesion because of activated macrophages that wall o the mutations in fucosyl transferase required microbes, forming granulomas. for synthesis of sialylated oligosaccharide (receptor for selectins) Myeloperoxida Decreased microbial killing because of Leukocyte se deficiency defective MPO-H2O2 system It is caused by the absence of adhesion DEFECTS IN COMPLEMENT SYSTEM sialyl-Lewis X, the fucose-containing deficiency 2 Defective classical pathway activation results ligand for E- and P-selectins, as a result C2, C4 of a defect in a fucosyl transferase, an in reduced resistance to infection and reduced deficiency enzyme that attaches fucose moieties to clearance of immune complexes protein backbones C3 deficiency Defects in all complement functions INHERITED DEFECT IN PHAGOLYSOSOME FUNCTION Deficiency of Excessive complement activation; clinical Decreased leukocyte functions because complement syndromes include angioedema, paroxysmal of mutations a ecting protein involved proteins hemoglobinuria Chediak DEFECTS IN TLR SIGNALING in lysosomal membrane tra c Higashi An autosomal recessive condition Defects in TLR3 Syndrome characterized by defective fusion of ○ a receptor for viral RNA, result in recurrent herpes phagosomes and lysosomes, resulting in simplex encephalitis, and defects in MyD88, the FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 10 adaptor protein downstream of multiple TLRs, are SEVERE COMBINED IMMUNODEFICIENCY (SCID) associated with destructive bacterial pneumonias. Severe combined immunodeficiency (SCID) spans a constellation of genetically distinct syndromes, all DEFECTS IN ADAPTIVE IMMUNITY having in common defects in both humoral and Defects in adaptive immunity are often subclassified cell-mediated immune responses on the basis of the primary component involved Primarily a ects the T-cells These immunodeficiencies result from abnormalities in A ected infants present with prominent thrush (oral lymphocyte maturation or activation candidiasis), extensive diaper rash, and failure to thrive Diseases involved: Without HSC transplantation (primary treatment), ○ Severe Combined Immunodeficiency death occurs within the first year of life. ○ X-linked Agammaglobulinemia Persons with SCID are extremely susceptible to ○ DiGeorge Syndrome recurrent, severe infections by a wide range of ○ Hyper-IgM Syndrome pathogens, including Candida albicans, Pneumocystis ○ Other defects in Lymphocyte Maturation jirovecii, Pseudomonas, cytomegalovirus, varicella, and ○ Common Variable Immunodeficiency a host of bacteria ○ Isolated IgA Deficiency Despite the common clinical manifestations, the ○ X-linked Lymphoproliferative disease underlying genetic defects are quite varied and in ○ Other defects in lymphocyte Activation many cases are unknown SCID defect resides in the T-cell compartment, with a secondary impairment of humoral immunity For both types of SCID: marked depletion of T-cell areas and in some cases both T-cell and B-cell zones. X-LINKED SCID Most Common form, 50%-60% of cases, more common in boys Genetic defect in the X-linked form is a mutation in the common γ-chain (γc) subunit of cytokine receptors ○ a signal-transducing component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21. IL-7 is required for the survival and proliferation of lymphoid progenitors, particularly T-cell precursors ○ Results in profound defect in T-cell development This is a summary picture that will explain what happens to Although B cells may be normal in number, antibody your B and T cells. The pluripotent stem cell will become a synthesis is impaired because of lack of T-cell help Common myeloid lymphoid progenitor cell and will either be IL-15 is important for the maturation and proliferation a Pro-B-cell or Pro-T-cell. of NK ○ Deficiency of NK cells Unable to produce your Pro T The thymus contains lobules of undi erentiated ADA Deficiency lymphocyte epithelial cells resembling fetal thymus When Pro T cell lymphocytes are Severe Combined not able to proceed to become an AUTOSOMAL RECESSIVE SCID Immunodeficiency immature T cell The most common cause of autosomal recessive SCID When immature T-cells are not able is a deficiency of the enzyme adenosine deaminase to di erentiate into mature forms, (ADA) most likely due to lack of thymus or ○ Proposed that deficiency of the enzyme leads to DiGeorge Syndrome isolated MHC Class II deficiency, accumulation of deoxyadenosine and its problems with your CD4 mature T derivatives (e.g., deoxy-ATP), which are toxic to cells rapidly dividing immature lymphocytes, especially X-linked Pre-B cell cannot proceed to those of the T-cell lineage Agammaglobulinemia become an Immature B cell ○ Remnants of Hassall’s corpuscles can be found (BTK) Other causes: Common Variable Immature B cells cannot proceed to ○ Mutations in recombinase-activating genes (RAG) Immunodeficiency Mature form ○ intracellular kinase called JAK3 (CVID) ○ T-cell antigen receptor and components of Hyper IgM Syndrome Increased IgM calcium channels (CD40 L) Only have 1 deficiency in IgA deficiency Immunoglobulin FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 11 SCID: MORPHOLOGY OTHER DEFECTS IN LYMPHOCYTE MATURATION Small thymus and devoid of lymphoid cells Bare Lymphocyte Syndrome In X-linked SCID, the thymus contains lobules of ○ Caused by mutations in transcription factors undi erentiated epithelial cells resembling fetal that are required for class II MHC gene thymus, whereas in SCID caused by ADA deficiency, expression. remnants of Hassall’s corpuscles can be found ○ Lack of class II MHC molecules prevents the development of CD4+ T cells, which are involved in X-LINKED AGAMMAGLOBULINEMIA cellular immunity and provide help to B cells Aka Bruton Agammaglobulinemia Other defects are caused by mutations in antigen Characterized by the failure of B-cell precursors receptor chains or signaling molecules involved in T- or (pro–B cells and pre–B cells) to develop into mature B B-cell maturation. cells X-linked agammaglobulinemia is caused by mutations HYPER-IGM SYNDROME in a cytoplasmic tyrosine kinase, called Bruton A ected patients have IgM antibodies but are tyrosine kinase (BTK) deficient in IgG, IgA, and IgE antibodies. ○ When BTK is mutated, the pre-B cell receptor Mature B cells are present, but they are incapable of Ig cannot deliver the signals that are needed for class switching and a nity maturation, because of a light chain rearrangement, and maturation is defect in CD4+ helper T cells or an intrinsic B-cell arrested. defect. Almost exclusively in males Approximately 70% of individuals with hyper-IgM The disease usually does not become apparent until syndrome have the X-linked form of the disease about 6 months of age, as maternal immunoglobulins ○ Caused by mutations in the gene encoding CD40L are depleted. located on Xq26 that interfere with CD4+ In most cases, recurrent bacterial infections of the helper T cell function. respiratory tract, such as acute and chronic The serum of persons with this syndrome contains pharyngitis, sinusitis, otitis media, bronchitis, and normal or elevated levels of IgM but no IgA or IgE and pneumonia extremely low levels of IgG. Almost always the causative organisms are Clinically, patients present with recurrent pyogenic Haemophilus influenzae, Streptococcus pneumoniae, or infections Staphylococcus aureus COMMON VARIABLE IMMUNODEFICIENCY CHARACTERISTICS: Relatively frequent entity encompasses a ○ B-cell are absent or decreased in circulation heterogeneous group of disorders ○ Depressed serum level of all immunoglobulins ○ Common feature is hypogammaglobulinemia, ○ Germinal centers of lymph nodes, Peyer patches, generally a ecting all the antibody classes but the appendix, and tonsils are underdeveloped. sometimes only IgG. ○ Absent Plasma Cells Diagnosis of common variable immunodeficiency is ○ T cell-mediated reactions are normal based on exclusion of other well-defined causes of ○ Paradoxical increase in autoimmune diseases decreased antibody production Contrast to X-linked agammaglobulinemia, most DIGEORGE SYNDROME individuals with common variable immunodeficiency AKA Thymic Hypoplasia have normal or near-normal numbers of B cells in the T-cell deficiency that results from failure of blood and lymphoid tissues. development of the thymus. Both intrinsic B-cell defects and abnormalities in ○ T cells mature in the thymus helper T cells–mediated activation of B cells may Third and fourth pharyngeal pouches → give rise to the account for the antibody deficiency in this disease. thymus, the parathyroids, some of the C cells of the Clinical manifestations of common variable thyroid, and the ultimobranchial body, do not develop immunodeficiency are caused by antibody deficiency, normally. and hence they resemble those of X-linked Absence of cell-mediated immunity is caused by low agammaglobulinemia numbers of T lymphocytes in the blood and lymphoid ○ X-linked agammaglobulinemia → no B cells tissues and poor defense against certain fungal and ○ Common variable immunodeficiency → have B viral infections cells Caused by a small germline deletion that maps to ○ Both of them are incapable of producing chromosome 22q11 immunoglobulins ○ DiGeorge syndrome is now considered a component of the 22q11 deletion syndrome, ISOLATED IGA DEFICIENCY TBX1, which is required for development of the caused by impaired di erentiation of naïve B branchial arch and the great vessels. lymphocytes to IgA-producing plasma cells. ○ IgA is the major antibody in mucosal secretions Most patients are asymptomatic FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 12 ○ Some patients may manifest infections occur in SECONDARY IMMUNODEFICIENCIES the respiratory, gastrointestinal, and urogenital Secondary (acquired) immune deficiencies may be tracts. encountered in individuals with: ○ Respiratory tract allergy and a variety of ○ Cancer autoimmune diseases ○ Diabetes When transfused with blood containing normal IgA, ○ Other metabolic diseases some patients develop severe anaphylaxis because ○ Malnutrition they recognize IgA as a foreign antigen. ○ Chronic infection ○ In persons receiving chemotherapy or radiation X-LINKED LYMPHOPROLIFERATIVE DISEASE therapy for cancer Inability to eliminate EBV ○ Immunosuppressive drugs to prevent graft ○ Eventually leading to fulminant infectious rejection or to treat autoimmune diseases mononucleosis and the development of B-cell (Transplant patients) tumors. In about 80% of cases, the disease is due to mutations CAUSE MECHANISM in the gene encoding an adapter molecule called Human Immunodeficiency Depletion of CD4+ Helper T SLAM-associated protein (SAP) Virus infection cells ○ Defects in SAP attenuate NK and T-cell activation Irradiation and Decreased Bone marrow and result in increased susceptibility to viral Chemotherapy treatments precursors for all Leukocytes infections. for Cancer Involvement of Bone Reduced site of leukocyte OTHER DEFECTS IN LYMPHOCYTE ACTIVATION marrow by Cancers development Mutations a ecting Th1 responses are associated with (Metastases, Leukemias) atypical mycobacterial infections ○ called Mendelian susceptibility to mycobacterial Metabolic derangements disease Protein-calorie malnutrition inhibit lymphocyte maturation Inherited defects in Th17 responses lead to chronic and function mucocutaneous candidiasis and bacterial infections of Decreased phagocytosis of Removal of spleen the skin → a disorder called Job syndrome. microbes IMMUNODEFICIENCIES ASSOCIATED WITH SYSTEMIC ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) DISEASE Caused by the retrovirus Human Immunodeficiency Virus (HIV) characterized by profound WISKOTT ALDRICH SYNDROME immunosuppression that leads to: X-linked disease characterized by (systemic problem) ○ Opportunistic infections thrombocytopenia, eczema, and (immunologic ○ Secondary neoplasms component) a marked vulnerability to recurrent ○ Neurologic manifestations infection Progressive loss of T lymphocytes in the peripheral blood and in the T-cell zones (paracortical areas) of the EPIDEMIOLOGY lymph nodes, with variable defects in cellular immunity. Men who have sex with men account for more than ○ Unable to make antibodies to polysaccharide 50% of the reported cases antigens, and the response to protein antigens is Heterosexual transmission, chiefly due to contact with poor members of other high-risk groups IgM levels are low, but IgG levels are normal. ○ Heterosexual spread of the virus is occurring most ○ Paradoxically the levels of IgA and IgE are often rapidly in female sex workers and in women in elevated. long-term marital or cohabitating relationships, Caused by mutations in the gene located at Xp11.23 particularly among adolescents. that encodes Wiskott-Aldrich syndrome protein Intravenous drug users with no previous history of (WASP) heterosexuality ○ Sharing needles ATAXIA TELANGIECTASIA HIV infection of the newborn Autosomal-recessive disorder characterized by ○ Dissemination through blood vessels abnormal gait (ataxia), vascular malformations ○ During birth (exposed to vaginal canal) (telangiectasia), neurologic deficits, increased ○ Breastmilk incidence of tumors, and immunodeficiency. Patients with Hemophilia, especially those who Gene responsible for this disorder is located on received large amounts of factor VIII or factor IX chromosome 11 and encodes a protein kinase called concentrates before 1985, make up about 0.5% of all ATM (ataxia telangiectasia mutated) cases Abnormalities in DNA repair resulting from ATM Recipients of blood and blood components, who are deficiency may impair the generation of antigen not hemophiliacs but who received transfusions of receptors. HIV-infected whole blood or components (e.g., ○ ATM is needed for DNA repair platelets, plasma) account for about 1% of patients. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 13 (Organs obtained from HIV-infected donors can also transmit the virus.) MODE OF TRANSMISSION Sexual transmission is the dominant mode of infection worldwide, accounting for more than 75% of all cases of HIV transmission ○ The virus is carried in the semen, and it enters the recipient’s body through abrasions in rectal or oral mucosa or by direct contact with mucosal lining cells. ○ Viral transmission occurs in two ways: 1. Direct inoculation into the blood vessels Diagram of HIV breached by trauma 2. Infection of DCs or CD4+ cells within the mucosa. Middle Core (2 RNA with viral enzymes) ○ In addition to male-to-male and male-to-female Surrounded by p17 matrix transmission, female-to-male transmission also p24 is the most abundant viral antigen p24 capsid occurs and is detected by an ELISA that is Parenteral transmission of HIV widely used to diagnose HIV infection ○ Occurred in three groups of individuals: Envelope - studded by a variety of proteins intravenous drug users (largest group), Outer layer These proteins are used for hemophiliacs who received factor VIII and diagnosis of HIV (gp120 and gp41) factor IX concentrates, and random recipients of blood transfusion GENOME OF HIV ○ Transmission occurs by sharing needles, syringes, and other paraphernalia contaminated with HIV-containing blood ○ Transmission of HIV by transfusion of blood or blood products, such as lyophilized factor VIII and factor IX concentrates, has been virtually eliminated Mother-to-infant transmission ○ Major cause of pediatric AIDS ○ Infected mothers can transmit the infection to their o spring by three routes: 1. In utero by transplacental spread (most common mode) 2. During delivery through an infected birth canal (most common mode) 3. After birth by ingestion of breast milk o MYTHS ABOUT HIV *ALL RETROVIRUS HAVE THESE* Casual personal contact? NO transmission gag Encode for Matrix protein p17 Mosquito bite NO transmission pol Encode Reverse Transcriptase Needle-stick injury THERE IS TRANSMISSION (low (Polymerase) chance) env Encode for gp160 Envelope protein Oral Sex There is a chance Accessory gene ○ Regulate synthesis and assembly of infectious ETIOLOGY: PROPERTIES OF HIV virus particles: tat, rev, vif, nef, vpr, vpu HIV is a non-transforming human retrovirus belonging PATHOGENESIS to the Lentivirus family The major target of HIV infection is the IMMUNE SYSTEM (CD4+) Most common type associated with AIDS in the The Central Nervous System (CNS) is also a ected HIV-1 United States, Europe, and Central Africa (Secondary target) Causes a similar disease principally in West Profound immune deficiency, primarily a ecting HIV-2 cell-mediated immunity, is the hallmark of AIDS Africa and India FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 14 NON-CYTOPATHIC form or Apportive HIV infection that activates Inflammasome pathway and leads to a form of cell death called PARAPOPTOSIS HIV infection of cells in lymphoid organs (spleen, lymph nodes, tonsils) causing progressive destruction of the architecture and cellular composition of lymphoid tissues Loss of immature precursors of CD4+ T cells Fusion of infected and uninfected cells with formation of syncytia (giant cells) can occur. Qualitative defects in T cells even in asymptomatic HIV infected persons Aside from the T-cells, other cells are also a ected E ects in Both T and B cells (Robbins) Lymphopenia Predominantly caused by death of the CD4+ T helper subset Decreased T-Cell Function in Vivo 1. Virus with membrane proteins gp41 and gp120 Preferential loss of activated and memory T cells 2. gp120 attach to CD4+ T-cells, induce conformational Decreased delayed type hypersensitivity change that will attract co-receptor CCR5 Susceptibility to opportunistic infections ○ CCR5 - needed for complete binding of HIV Susceptibility to neoplasms 3. Penetration of gp41 4. Membrane fusion - viral envelope will fuse with the cell Altered T-Cell Function in Vitro membrane Decreased proliferative response to mitogens, alloantigens, There is access of viral genome to cytosol and soluble antigens 5. Activation of Reverse Transcriptase and Reverse Decreased cytotoxicity Transcriptase synthesis of proviral DNA Decreased helper function for B-cell antibody production 6. Viral DNA will find its way to the nucleus and integrate Decreased IL-2 and IFN-y production the provirus into the host of the cell gene Polyclonal B-Cell Activation 7. With every expression there will be HIV viral transcript. Hypergammaglobulinemia and circulating immune Triggers are: complexes Cytokines - produced by inflammation, every Inability to mount de novo antibody response to new inflammation or infection signals viral genome to antigens proliferate Poor responses to normal B-cell activation signals in vitro ○ The cytokine activation of the cell leads to Altered Monocyte or Macrophage Functions the transcription of the viral genome and Decreased chemotaxis and phagocytosis transfer into cytosol Decreased class II HLA expression 8. This will now be Translated, there will now be Synthesis Diminished capacity to present antigens to T cells and Assembly of virion core structure 9. Exported PATHOGENESIS OF CNS INVOLVEMENT 10. Budding and Release new HIV virion The clinical syndrome of CNS abnormalities is called Preferentially a ects ACTIVATED T CELLS HIV-associated neurocognitive disorder (HAND) However, does it a ect immature or naive resting T Microglia, cells in the CNS that belong to the cells? macrophage lineage, are the predominant cell types in ○ Usually NO, because the Naive T cells contain an the brain that are infected with HIV enzyme that induces mutations at the HIV neurologic deficit is caused indirectly by viral products genome and by soluble factors produced by infected microglia Repeated process until cell death = either undergo ○ IL-1, TNF, and IL-6. Necrosis or Apoptosis due to consumption of resources Nitric oxide induced in neuronal cells by gp41 has been of CD4+ cell implicated Direct damage of neurons by soluble MECHANISM OF T CELL DEPLETION HIV gp120 has also been postulated Loss of CD4+ T cells is mainly caused by the DIRECT CYTOPATHIC EFFECTS of the replicating virus Chronic activation of uninfected cells, responding to HIV itself To infections that are common in individuals with AIDS, leading to apoptosis of these cells FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PATHOLOGY A | DR. DARYL ALVIN REQUISO 15 PROPOSED HIV PATHOGENESIS CLINICAL COURSE OF HIV This is a graph showing Viremia and CD4+ T cells ○ Yellow line = Viral copies (viremia) ○ Blue line = CD4 count ○ X axis = Time (weeks, years) During the early period after primary infection, there is dissemination of virus, development of an immune response to HIV, and often an acute viral syndrome. During the period of clinical latency, viral replication continues, and the CD4+ T-cell count gradually decreases until it reaches a critical level below which there is a substantial risk of AIDS-associated diseases. Over 3-6 weeks, viremia will develop and there is also a drop in your CD4+ count but the body will response How will it spread to the rest of the body? and control it Initially, the infection is at the mucosal tissue that will Eventually, there will be a decrease in your viral load be presented by the dendritic cells to the CD4 T cells. with an increase of your CD4+ count Once presented, the HIV virus will enter and cause the However, the patient will now enter clinical latency death of mucosal memory CD 4 T cells which can last for several years The virus will then be transported into the lymph nodes, Overtime, the damage is still progressive, CD4+ will promoting the establishment of the virus in the slowly decrease and the viral count is stable lymphoid tissue Continuous decreasing of CD4+ will result to increase Once the virus has been established in the lymph node, viral count it will spread throughout the body resulting to viremia Eventually, the patient will develop symptoms and (increased copy of viral copy in the bloodstream) when the CD4+ is almost depleted, viremia will The body will initially respond by producing Anti-HIV continuously increase and can ultimately lead to death antibodies or HIV-specific CTLs, leading to a partial control of your viral replication The patient will enter a period of clinical latency, wherein there will be establishment of chronic infection ○ Virus is concentrated in lymphoid tissues with low-level virus production Overtime, depending on the patient’s immune system, around 5 to 10 years, the damage will be severe since the body cannot keep up and cause destruction of the lymphoid tissue ○ Severe - increased viral replication When that happens, there will be an increase again in This graph just represents the first one to rise and their the viral replication, making it become full blown AIDS corresponding patterns In AIDS, there will be destruction of lymphoid tissues ○ Red - Viral particles and depletion of CD4+ T cells ○ Purple - CTLs specific for HIV peptides ○ Green - Anti-p24 antibody ○ Yellow - Anti-envelope antibody