Immunologic Disease Gen Path 2024 PDF

Diseases of the Immune System Tom Fry, DDS Pathology: Immunologic Disease Today’s topics Review of the cellular components and basic functions of the immune system Review of hypersensitivity reactions Mechanisms of autoimmunity and autoimmune disorders Transplantation medicine, HLA compatibility and...

Diseases of the Immune System Tom Fry, DDS Pathology: Immunologic Disease Today’s topics Review of the cellular components and basic functions of the immune system Review of hypersensitivity reactions Mechanisms of autoimmunity and autoimmune disorders Transplantation medicine, HLA compatibility and post-transplant complications Congenital and acquired immune deficiencies Pathology: Immunologic Disease Immune cells of interest T lymphocytes Mature in the thymus Must be activated by an antigenpresenting cell in order to differentiate and proliferate CD4+ helper cells stimulate immune responses, especially in B-cells, by releasing cytokines CD8+ cytotoxic T lymphocytes (CTLs) directly kill virus-infected cells and tumor cells Regulatory T lymphocytes suppress immune function Pathology: Immunologic Disease Immune cells of interest B lymphocytes Mature in the bone marrow Must be activated by a CD4+ T helper cell in order to differentiate and proliferate Activated B cells differentiate in to plasma cells, producing antibody in large quantities in response to infection Pathology: Immunologic Disease Immune cells of interest Natural killer cells Lymphoid cells that are part of the innate immune response and do not require activation by a helper or antigen presenting cell Antigen presenting cells Examples: dendritic cells and macrophages Specialized innate immune cells that capture antigens and present them to naïve T cells, hence activating them Form a bridge between the innate and adaptive immune system Pathology: Immunologic Disease The normal immune response Pathology: Immunologic Disease Innate immunity Recognizes a limited number of specific common antigens (thousands) and responds to them rapidly Composed of epithelial barriers, phagocytes (macrophages and neutrophils), dendritic cells, natural killer cells and complement Pathology: Immunologic Disease Innate immunity Innate immune cells respond to common molecular patterns associated with infection and cell death Pathogen-associated molecular patterns (PAMPs) Damage-associated molecular patterns (DAMPs) Toll-like receptors detect extracellular threats, while NODlike receptors detect intracellular ones Pathology: Immunologic Disease Innate immunity Cytokines and complement activation cause inflammation, leukocyte recruitment, pathogen destruction, and elimination of damaged cells Type I interferons activate innate antiviral mechanisms Pathology: Immunologic Disease Adaptive immunity Can recognize and respond to a wide range of foreign substances, but recognition of a new substance takes time Once an antigen has been recognized, a reservoir of memory cells persists, and can respond rapidly in the event of a second insult or infection Pathology: Immunologic Disease Adaptive immunity Two branches: humoral and cellular Humoral: B-lymphocytes that produce antibody that primarily acts on extracellular pathogens Cellular: T-lymphocytes that respond to intracellular pathogens T-helper lymphocytes activate and sustain T- and B- cell responses using cytokines Pathology: Immunologic Disease Major histocompatibility complexes Used by cells to present antigen to immune cells and trigger an immune response, if indicated Coded by human leukocyte antigen (HLA) genes, which are highly variable identify the cells of an individual as “self” Two types of MHC: Class I and Cass II Pathology: Immunologic Disease Major histocompatibility complexes Class I MHC molecules are expressed on the surface of all nucleated cells Present to CD8+ CTLs, which induce apoptosis in infected/affected cells Coded by HLA-A, HLA-B and HLA-C Pathology: Immunologic Disease Major histocompatibility complexes Class II MHC molecules are expressed on antigen presenting cells and B cells Present to CD4+ Helper Tcells, which can activate or potentiate immune responses Coded by HLA-DP, HLA-DQ and HLA-DR Pathology: Immunologic Disease Hypersensitivity Immunologically mediated tissue damage – not just allergies! Can be caused by: Autoimmunity: reactions against self antigens Reactions against microbes Granulomas (tuberculosis) Immune complexes (postinfectious glomerulonephritis, lupus) Cross-reactivity (rheumatic heart disease, long Covid?) Reactions against environmental antigens— environmental or pharmacologic Pathology: Immunologic Disease Hypersensitivity Angioedema Mucous membrane pemphigoid Erythema multiforme Pathology: Immunologic Disease Type I – Allergy Pathologic response of IgEmediated immunity First exposure: IgE classswitching B cells that are reactive to an allergen are activated and become IgE-secreting plasma cells IgE binds to mast cells Second esposure: Mast cells with bound reactive IgE release inflammatory mediators that cause an immediate reaction Pathology: Immunologic Disease Type I - Angioedema Angioedema and other type I hypersensitivity responses to dental materials and medications are relatively uncommon, but do occur The most common type of angioedema is a type I hypersensitivity reaction Affected tissues swell and sometimes become itchy due to allergic inflammation Pathology: Immunologic Disease Type I - Angioedema Can be life-threatening if swelling obstructs the airway If angioedema is observed during dental treatment, treatment should be stopped, the allergen identified, and treatment modified to forego the allergen Non-life-threatening cases are managed with diphenhydramine and rest Pathology: Immunologic Disease Type II – Antibodies Cased by antibodies directed against antigens on normal cells or other tissue components Antibody causes hypersensitivity by: Triggering opsonization of normal cells (e.g. autoimmune hemolytic anemia) Activating the compliment system (e.g. myasthenia gravis) Inducing cellular dysfunction (e.g. Grave’s disease) Pathology: Immunologic Disease Type II – Vesiculobullous disease Mucous membrane pemphigoid and pemphigus vulgaris are type II hypersensitivity-mediated autoimmune disorders that often affect the oral mucosa Mucous membrane pemphigoid attacks hemidesmosomes in mucosal epithelium, including in the oral cavity Pemphigus vulgaris attacks desmosomes in epithelia throughout the body, and can be life-threatening Affected tissues develop bullae, desquamation, and inflammation Pathology: Immunologic Disease Type III – Immune complexes Caused by antibody-antigen complexes that deposit in blood vessels, leading to compliment activation and inflammation Can be caused by a foreign antigen (usually microbial) or by self-antigens (often nuclear antigens, as in SLE) Often systemic, as these complexes can deposit throughout the body Complexes preferentially deposit in the kidney, joints and small blood vessels Pathology: Immunologic Disease Type III – Systemic lupus erythematosus Causes kidney damage, anemia and polyarthritis Can also cause lichenoid lesions of the oral mucosa Oral lupus lesions are a precancerous condition, and patients should be monitored routinely for dysplasia and SCC Pathology: Immunologic Disease Type IV - T lymphocytes Can be mediated by CD4+ or CD8+ T lymphocytes CD4+ lymphocytes induce an inflammatory response that takes 24-48 hours and is known as a delayed-type hypersensitivity (e.g. rheumatoid arthritis, inflammatory bowel disease) CD8+ lymphocytes directly kill antigen-expressing target cells (e.g. type I diabetes) Pathology: Immunologic Disease Type IV – Erythema multiforme Causes acute ulceration of the mucous membranes and target lesions on the skin Flares last 2-4 weeks, and are commonly caused by infections (especially HHV) and medications (NSAIDs, antibiotics, others) Severe or non-resolving cases may be Stevens-Johnson syndrome, which can be lifethreatening and require intensive management Pathology: Immunologic Disease Type IV – Erythema multiforme Treatment includes palliative care (analgesics, topical anesthetics), systemic and topical steroid therapy, and antiviral treatment when indicated Patients with recurrent, virallyinduced EM may require antiviral prophylaxis Pathology: Immunologic Disease Autoimmune diseases A reaction against self antigens by the immune system 5-8% of the US population is estimated to suffer from an autoimmune illness Can be organ-specific (Graves disease) or systemic (SLE) Pathology: Immunologic Disease Immunologic tolerance Term for the mechanisms that prevent a diverse and randomly-generated adaptive immune system from reacting to self-antigens Mutations and therapies that affect these mechanisms increase an individual’s risk of developing an autoimmune disease However, the exact failures of selftolerance that lead to common autoimmune diseases are not known Pathology: Immunologic Disease Immunologic tolerance Several mechanisms of self-tolerance are known in humans: Elimination of self-reactive lymphocytes during maturation in the thymus and bone marrow Suppression of lymphocyte activation by regulatory T cells Inhibition of lymphocyte activation by inhibitory receptors Programmed death of self-reactive lymphocytes mediated by the Fas receptor Pathology: Immunologic Disease Mechanisms of Autoimmunity Genetics The specific genetic causes of common autoimmune disorders are unknown, but these diseases do cluster in families Many mutations that are associated with multiple disorders, suggesting that general mechanisms are more often affected than specific ones Pathology: Immunologic Disease Mechanisms of Autoimmunity Infections Microbial infections can cause tissue necrosis and inflammation that upregulate APCs and T cells, favoring a breakdown of T cell tolerance Microbes may share cross-reacting epitopes with self antigens that can lead to immunologic cross-reaction Example: rheumatic heart disease is caused by a crossreactive antibody to streptococci Pathology: Immunologic Disease Mechanisms of Autoimmunity Normal gut and skin microbiome May influence, or be influenced by, the relative proportions of effector/killer and regulatory T cells We don’t know which bacteria are problematic, or how to alter the microbiome effectively Environmental factors Sunlight, smoking and injury can modify or expose self-antigens Pathology: Immunologic Disease Mechanisms of Autoimmunity Female Sex Most autoimmune diseases are more common in phenotypic females Is this due hormonal differences? An altered immune system in response to the need to carry a fetus to term? We don’t really know. Pathology: Immunologic Disease Common Autoimmune Disorders Systemic lupus erythematosus (SLE) Rheumatoid arthritis (discussed with other joint disease in chapter 19) Sjögren syndrome Systemic sclerosis (scleroderma) Pathology: Immunologic Disease Systemic lupus erythematosus (SLE) A highly variable, multisystem disorder Characterized by the production of autoantibodies, especially antinuclear antibodies (ANAs) Type III hypersensitivity-mediated Often affects the kidney, small vessels and joints Fairly common – up to 400 patients per 100,000 in certain populations (African- and Latin-Americans) Strong female predilection that is more pronounced during reproductive years 9:1 F:M ratio at ages 17-55 2:1 F:M ratio in childhood and after 65 years of age Pathology: Immunologic Disease Systemic lupus erythematosus (SLE) Autoantibodies in SLE Can be directed against nuclear and cytoplasmic components (intracellular) or surface cell antigens (extracellular) Generic ANAs are found in nearly all SLE patients, but are not specific Anti-dsDNA antibodies are specific for SLE Type(s) of antibodies present in an individual can be linked to specific SLE-related pathologies Pathology: Immunologic Disease SLE Pathogenesis Abnormalities of T helper and B lymphocytes lead to defective tolerance Tissue damage causes apoptosis of cells Inadequate clearance of apoptotic cell nuclei leads to a large burden of nuclear antigens Self-reactive lymphocytes are stimulated by nuclear self antigens to produce auotantibodies Immune complexes form around self-antigens and deposit in the tissues Deposited immune complexes induce local inflammation, which enhance immune response and further induce apoptosis, feeding the cycle of apoptosis, self-recognition, complex deposition and inflammation Pathology: Immunologic Disease Common Clinical Features Essentially all patients with SLE present with hematologic abnormalities. Anemia and/or thrombocytopenia with associated signs/symptoms Renal involvement may produce a variety of findings related to kidney dysfunction (see chapter 12) Skin rash (malar rash) Arthritis (non-deforming) Fatigue Weight loss More! Pathology: Immunologic Disease A “Typical” SLE Patient Young adult female with one some or all of the following: Malar rash (“butterfly rash”) on the face Fever of unknown origin Pain without deformity in one or more joints Chest pain Photosensitivity Pathology: Immunologic Disease Orofacial Manifestations Oral lichenoid lesions Red and white, reticular (lacy) lesions that can occur anywhere in the mouth Secondary Sjogren syndrome (more later) Pathology: Immunologic Disease Clinical Course The clinical SLE course is usually relapsing and remitting over years or decades. Treatment can vary according to affected systems and severity of disease Disease flares are usually treated with corticosteroids or immunosuppressants 5/10-year survival is 90%/80% Pathology: Immunologic Disease Sjögren Syndrome A chronic progressive disease characterized by dry eyes and dry mouth Caused by autoimmune destruction of the lacrimal and salivary glands by T helper and B cells Autoantibodies help diagnose, but are not always detectable 60% of cases present with another autoimmune disease (RA or SLE) Most commonly occurs in women (9:1 F:M) between the ages of 50 and 60 Pathology: Immunologic Disease Sjögren Syndrome Two important diagnostic tests: Salivary gland biopsy showing lymphocytic infiltrate, measured by “focus score” (focus score >/=1 meets criteria SS-A (anti-nuclear antigen) serum testing 75% of SS patients are positive for rheumatoid factor and 50-80% are positive for generic ANAs, but these are not diagnostic Pathology: Immunologic Disease Sjögren Syndrome Common presentation can include Burning or dryness of eyes or mouth Reported lack of tears or saliva Difficulty speaking, eating or swallowing Chronic or recurrent oral candidiasis Cyclic or persistent enlargement of the parotid glands Other clinical manifestations include Joint pain without deformity Peripheral neuropathies Chronic or recurrent oral candidiasis A dry cough or chronic throat irritation Patients with SS are at increased risk of developing a Bcell MALT lymphoma that often manifests as a unilateral swelling of the neck or face Patients with SS often develop significant dental and periodontal disease and require special management! Pathology: Immunologic Disease Sjögren Syndrome Common presentation can include Burning or dryness of eyes or mouth Reported lack of tears or saliva Difficulty speaking, eating or swallowing Chronic or recurrent oral candidiasis Cyclic or persistent enlargement of the parotid glands Pathology: Immunologic Disease Sjögren Syndrome Other manifestations: Joint pain without deformity Peripheral neuropathies Chronic or recurrent oral candidiasis A dry cough or chronic throat irritation Patients with SS are at increased risk of developing a B-cell lymphoma Patients with SS often develop significant dental and periodontal disease secondary to dry mouth Pathology: Immunologic Disease Systemic Sclerosis (Scleroderma) Causes excessive fibrosis in multiple tissues, obliterative vascular disease Characterized by striking skin changes, especially thickening of the skin 3:1 F:M ratio Peak incidence between 50 and 60 years of age 5- and 10- year survival rates are 75% and 63% Pulmonary involvement is the most common cause of death Pathology: Immunologic Disease Systemic Sclerosis Diffuse systemic sclerosis is characterized by widespread skin involvement, rapid progression, early visceral involvement, higher morbidity and mortality Pathology: Immunologic Disease Systemic Sclerosis Limited systemic sclerosis (CREST syndrome) is limited to mild skin involvement, late involvement of the viscera, lower morbidity and mortality CREST Calcinosis – calcium deposits in the skin Raynaud phenomenon Esophageal dysmotility Sclerodactyly – fibrotic changes of the skin of the hands and fingers Telangectasia – superficial, widened cutaneous capillaries/venules Pathology: Immunologic Disease Pathogenesis Likely results from three interrelated processes: Self-reactive CD4+ T cells release cytokines that cause inflammation and stimulate fibroblast activity Repeated cycles of endothelial damage and platelet accumulation cause fibrosis and narrowing of blood vessels, leading to ischemic injury and scarring. Lungs are frequently involved, leading to pulmonary hypertension Hyperstimulation of fibroblasts by immune cells, and scarring following ischemic damage lead to widespread fibrosis Pathology: Immunologic Disease Clinical Features Cutaneous: generalized thickening of the skin that can reduce joint mobility, often most severe in the hands Oral involvement: microstomia (see right) Ankyloglossia – thickening and shortening of the lingual frenum, may limit tongue movement Pathology: Immunologic Disease Clinical Features GI: dysphagia, malabsorption of nutrients Pulmonary: respiratory difficulty, pulmonary hypertensionàheart failure Caridovascular: severe hypertension, myocardial fibrosisàheart failure Renal: kidney failure 2/2 severe hypertension Pathology: Immunologic Disease Clinical Features Serum ANA Anti-Scl 70 is specific to systemic sclerosis, with greater risk of diffuse disease w/pulmonary fibrosis and vascular disease Anti-centromere antibody is associated with a higher risk of CREST syndrome Pathology: Immunologic Disease Immunology of Transplantation Non-self tissue and cells transplanted from a donor are attacked and destroyed under normal circumstances This rejection of an exogenous transplant is a major barrier to survival of the transplant The most important non-self antigens that result in rejection are HLA molecules Graft rejection is mitigated by careful selection of compatible donors and immunosuppression Hematopoietic stem cell or bone marrow transplants can result in a rejection of host tissues by transplanted immune cells, resulting in graft vs. host disease Pathology: Immunologic Disease HLA and Rejection Human Leukocyte Antigen (HLA) is a highly variable portion of the MHCI and MHC2 receptors, which play an essential role in antigen presentation and immunity HLA loci are used by the immune system to recognize host cells and differentiate them from foreign cells The high variability of these regions allows for individual immune systems to easily make this distinction, even within a relatively homogenous population Foreign HLA triggers a robust immune response Pathology: Immunologic Disease HLA and Rejection Following transplantation, the recipient’s T cells recognize donor HLA antigens by two pathways: Direct presentation to T cells by graft cells Indirect presentation to T cells by host APCs that have captured graft antigen (macrophages, dentritic cells, B cells) Pathology: Immunologic Disease HLA and Rejection Direct presentation is thought to be more important in acute rejection Indirect presentation is thought to be more important in chronic rejection In rare (now) cases, a memory response to a graft antigen can result in a hyperacute rejection Pathology: Immunologic Disease Hyperacute Rejection Occurs when the host has preformed antibodies specific for antigens on graft endothelial cells These antibodies can be specific for blood group antigens or antibodies specific for allogeneic HLA molecules These antibodies can form in response to blood transfusions, pregnancy or previous organ transplantation Pathology: Immunologic Disease Hyperacute Rejection Immediately after blood flow is restored to the graft, antibodies bind to antigens on the graft endothelium and activate the complement and clotting systems, ultimately resulting in collapse of blood flow and ischemic necrosis of the graft Due to this rapid cutoff of blood flow and ischemic failure, this is sometimes referred to as a “white graft” Today, this type of rejection is rare, because patients are matched for blood type and recipients are tested for antibodies against prospective donor cells Pathology: Immunologic Disease Acute Rejection Mediated by T cells and/or antibodies that recognize and are activated by antigens in the graft Usually occurs within days or weeks after transplantation, but can also occur months or years later, as immunosuppression is tapered or stopped Pathology: Immunologic Disease Acute Rejection Two mechanisms: Cellular rejection, mediated by CD8+ and CD4+ T cells, which can damage the graft or its vasculature Antibody-mediated rejection, mediated by B cells and CD4+ cells, can damage the vascular endothelium of the graft directly or via complement activation Immunosuppressants can prevent or limit acute rejection, but are generally more effective against cellular rejection Pathology: Immunologic Disease Chronic Rejection Graft damage that occurs over months or years, leading to progressive loss of graft function Results in interstitial fibrosis and narrowing of graft blood vessels T cells react against graft antigens by secreting cytokines that stimulate proliferation of fibroblasts Autoantibodies can contribute to chronic rejection by causing intravascular inflammation Immunosuppression can only slow this process Given enough time, all solid organ transplants will eventually fail due to chronic rejection Pathology: Immunologic Disease Increasing Graft Survival HLA Matching Matching HLA on MHCI (A, B, C) results in CD8+ T cell tolerance, lower cellular immune response Matching HLA on MHCII (DP, DQ, and DR) results in CD4+ T cell tolerance, lower cellular and humoral immune response 25% of siblings have identical HLA loci (twins 100%) Immunosuppression Required for all transplants (except twins) Anti-rejection medications can extend the life of an allograft for years to decades Patients are at higher risk of a range of illnesses Pathology: Immunologic Disease Hematopoietic Stem Cell Transplant Used to treat: Hematologic malignancies (leukemia, lymphoma) Bone marrow failure (aplastic anemia) Genetic stem cell defects (sickle cell anemia, thalassemia, primary immunodeficiencies) Pathology: Immunologic Disease Hematopoietic Stem Cell Transplant Historically obtained from bone marrow, but now harvested from peripheral blood after course of hematopoietic growth factors Total body irradiation and/or chemotherapy destroy the host immune system so that the graft cells can recolonize the marrow space and seed a new population of HSCs Pathology: Immunologic Disease Graft-vs-Host Disease Occurs when transplanted HSCs recognize alloantigens in the host and attack host tissues Almost always occurs after HSCT, but can rarely occur after transplantation of organs rich in lymphoid cells (e.g. liver or intestine) Pathology: Immunologic Disease Graft-vs-Host Disease CD4+ and CD8+ T cellmediated damage causes inflammation and host cell death HLA matching can prevent or limit severity Can be acute or chronic Elimination of donor T cells before transplantation eliminates the disease, but cancer recurrence, graft failures, and Bcell lymphomas increase Pathology: Immunologic Disease Graft-vs-Host Disease Acute GVHD Characterized by necrosis in three organs: liver, skin and GI tract Destruction of bile ducts à jaundice Gut ulceration à bloody diarrhea Skin: a rash that spreads from the neck, ears, palms and soles and becomes generalized (upper right) Often fatal: about 1/3 of patients who develop acute GVHD die within one year of transplant Pathology: Immunologic Disease Graft-vs-Host Disease Chronic GVHD Skin lesions and dermal fibrosis that can mimic systemic sclerosis Can involve gut, liver, salivary glands Patients often develop lichenoid lesions (lower right), dry mouth and parotid enlargement Increased risk of several malignancies, including oral SCC Pathology: Immunologic Disease Immunodeficiency Can be primary/congenital or secondary/acquired Primary immunodeficiencies are caused by genetic defects Secondary immunodeficiencies can be caused by immunosuppression, chemoradiation, infection, cancer, malnutrition, old age… Pathology: Immunologic Disease Primary Immunodeficiency Primary (genetic) immunodeficiencies are largely caused by defects in the acquired immune system SCID XLA DiGeorge Syndrome Primary innate immunodeficiencies are primarily related to defects in APCs and complement. We will not discuss these today. Pathology: Immunologic Disease Severe Combined Immunodeficiency (SCID) An umbrella term for immunodeficiencies related to impaired maturation of T lymphocytes and/or B lymphocytes Results in defective humoral and cellular immunity Can be X-linked or autosomal recessive Occurs in 1 in 65,000-100,000 infants, but is 20-30 times more common in Navajo and Apache Native Americans Pathology: Immunologic Disease Severe Combined Immunodeficiency (SCID) Presents in infancy with recurrent, severe infections Infants can develop a GVHD-type rash immediately after birth, caused by circulating maternal T-cells that the host is unable to eliminate Treatment: hematopoietic stem cell transplant Left untreated, SCID is fatal within the first year of life Pathology: Immunologic Disease X-Linked Agammaglobulinemia (XLA) Also known as Bruton disease X-linked Characterized by failure of pre-B cells to mature into B cells, resulting in an absence of antibodies (gamma globulin) in the blood B cell counts are low, germinal centers are absent from lymphoid tissues T cell numbers and responses may be normal Pathology: Immunologic Disease X-Linked Agammaglobulinemia (XLA) Generally does not present until ~6 months of age, due to circulating maternal antibodies Recurrent bacterial, viral and protozoal infections Autoimmune diseases occur in up to 35% of patients Treatment: intravenous immunoglobulin (IVIG) Pathology: Immunologic Disease DiGeorge Syndrome Caused by a genetic defect in the development of the thymus, resulting in deficient T cell maturation Caused by a chromosomal deletion (22q11.2) that can also cause velocardiofacial syndrome, increase patient risk of bipolar disorder and schizophrenia T cells are absent in the lymphoid tissues and peripheral blood B cell and serum immunoglobulin levels are normal Pathology: Immunologic Disease DiGeorge Syndrome Infants with DiGeorge syndrome are highly susceptible to bacterial, viral and protozoal infections Treatment: patients with residual thymus generally improve spontaneously with age and do not require treatment Cases with complete loss of thymus have been treated with thymus transplant Pathology: Immunologic Disease Secondary Immunodeficiencies A wide variety of illnesses and treatments can cause secondary immunodeficiency Cancer, especially hematologic cancers Chemotherapy Radiation therapy Immunosuppressive medications Diabetes Malnutrition Infection And more! Pathology: Immunologic Disease HIV – Viral Features A retrovirus from the lentivirus family Two HIV viruses, HIV-1 and HIV-2, cause similar illnesses Primarily infects CD4+ T helper cells, which are killed by the virus Can latently infect memory Th cells, providing a long-lived reservoir of virus, despite a strong immune response Can also infect macrophages, which may serve as a reservoir for virus when CD4+ cells are depleted Pathology: Immunologic Disease HIV – Course of Infection Virus enters the body, most commonly via mucosal surfaces or IV injection The acute phase is characterized by nonspecific flu-like symptoms arising within 3-6 weeks of infection and lasting 2-4 weeks This phase occurs in 40-90% of infections, with the rest being asymptomatic The chronic phase can last many years, and has few or no clinical manifestations. During this phase, CD4+ counts steadily decline Pathology: Immunologic Disease HIV – Course of Infection AIDS develops once the host immune system becomes debilitated to the point that it breaks down Long-lasting fever, fatigue, weight loss and diarrhea Opportunistic infections, neoplasms, and neurologic defects emerge Pathology: Immunologic Disease HIV – Course of Infection Patients are diagnosed with AIDS when their CD4+ count measures below 200 cells/uL, or when they develop an AIDS-defining condition Examples: opportunistic infections (Pneumocystis jirovecii pneumonia, cytomegalovirus), and certain cancers (Kaposi sarcoma) Once diagnosed with AIDS, patients are considered to have AIDS regardless of future disease status Pathology: Immunologic Disease HIV – Oral Manifestations Oral Hairy Leukoplakia is a benign lesion of the lateral tongue that is caused by Epstein-Barr virus (HHV-4) Presents as a shaggy, corrugated white lesion of the lateral border of the tongue (bottom right) Kaposi sarcoma (middle right) is a vascular neoplasm caused by HHV-8 that is strongly associated with AIDS Patients with AIDS are more likely to have oral manifestations of KS (70% vs. 20%) Lesions present as deep red, brown or blue patches or growths of the hard palate, ginigva or tongue Frequent, fulminant oral infections – candidiasis, herpes simplex, necrotizing ulcerative gingivitis, human papillomavirus, aphthous stomatitis (top right) Severity of infections correlates with degree of immunosuppression Presentations can be atypical and more widespread than expected in immunocompetent patients Pathology: Immunologic Disease HIV – Oral Manifestations Frequent, fulminant oral infections – candidiasis, herpes simplex, necrotizing ulcerative gingivitis, human papillomavirus, aphthous stomatitis (top right) Severity of infections correlates with degree of immunosuppression Presentations can be atypical and more widespread than expected in immunocompetent patients Pathology: Immunologic Disease HIV – Oral Manifestations Kaposi sarcoma (middle right) is a vascular neoplasm caused by HHV-8 that is strongly associated with AIDS Patients with AIDS are more likely to have oral manifestations of KS (70% vs. 20%) Lesions present as deep red, brown or blue patches or growths of the hard palate, ginigva or tongue Pathology: Immunologic Disease HIV – Oral Manifestations Oral Hairy Leukoplakia is a benign lesion of the lateral tongue that is caused by Epstein-Barr virus (HHV-4) Presents as a shaggy, corrugated white lesion of the lateral border of the tongue (bottom right) Pathology: Immunologic Disease HIV – Treatment Antiretroviral Therapy (ART) has radically changed the clinical course of aids With ART, HIV levels can become undetectable, and CD4+ count can return to normal With ART, the death rate from AIDS in the USA has been reduced by 75%, and many AIDSdefining conditions are now uncommon Pre-exposure prophylaxis (PrEP) is very effective at preventing infection in uninfected individuals at high risk of developing aids There is still no cure for HIV, and no HIV vaccine Pathology: Immunologic Disease THANK YOU Pathology: Immunologic Disease