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GI Pathology in Innate and Acquired Immunodeficiency Arzu Ensari, MD, PhD Ankara University Medical School Department of Pathology Why GIT ? • Largest lymphoid organ & primary barrier • 2nd commonly affected system (5% - 50%) Mucosal Immunology (2008) 1, 31–37 Aquired/adaptive immune system Innate immune system • Neutrophils , macrophages dendritic cells, NK cells • Natural barriers (skin, GI & respiratory mucosa) • Antimicrobial agents, opsonins (complement), cytokines • Preformed in germline • Nonspecific immunity • No memory T cells B cells Developes throughout life Specific immunity (cellular & humoral) • DNA rearrangement & memory • Amplification of immune response upon re-exposure • • • • Primary immunodeficiencies (PID) Acquired immunodeficiencies (AID) • Rare • Inherited defects • >150 genes >200 phenotypes • Defects in B, T cells or in innate immune system • Early in life • More common • HIV/AIDS, malignancy, transplants, drugs, metabolic disorders, malnutrition, environmental stress • Later in life J Allergy Clin Immunol. 2014 Jun;133(6):1651-9 SCID-AR CVID sIgA X-linked AGG Bruton’s SCID-AR SCID-X-linked DiGeorge Humoral ID • Agammaglobulinemia: X-linked and autosomal recessive • Common variable immune deficiency • IgG subclass deficiency • Selective IgA deficiency • Specific antibody deficiency • Transient hypogammaglobulinemia of infancy • Other antibody deficiency disorders Cellular ID • • • • • • Innate ID • • • • • Chronic granulomatous disease Hyper IgE syndrome Complement deficiencies Innate immune defects NEMO deficiency syndrome Severe combined immunodeficiency Wiskott-Aldrich syndrome Hyper IgM syndromes Ataxia Telengiectasia DiGeorge syndrome Other primary cellular immunodeficiencies PID •Adults: CVID & sIgA deficiency •Children: severe combined ID •Chronic granulomatous disease Acquired ID •Infections •HIV/AIDS •Immunosuppressive Tx •RT/ChT •Transplantation ID & GIT Inflammation Mimics other GI disorders Normal histology Infection Autoimmune disorders Neoplasia GI pathology in ID (site-dependent) Nonspecific morphology + infection Specific morphology of ID Complications secondary to Tx Changes the course of GI disorders Neoplasia No change Specific morphology Nonspecific morphology Normal biopsy Absence of plasma cells or lymphocytes Altered B or T cell subsets Diffuse nodular lymphoid hyperplasia Esophagitis Atrophic gastritis Erosions/ulcers Enteropathy Enterocolitis Demonstration of microorganism Neoplasia Adenocarcinoma Lymphoma: Burkitt’s & Diffuse large B cell Kaposi’s sarcoma Selective IgA deficiency • Most common (1 in 300-700) • Defective terminal maturation of B cells into IgA-secreting plasma cells • Majority asymptomatic • Association with Giardiasis, coeliac disease, NLH, IBD, pernicious anemia, gastric/ colorectal adenocarcinoma • Paucity of plasma cells • Absence of IgA-secreting plasma cells (IHC) IgA Common Variable Immune Deficiency (CVID) • 2nd most common (1 in 25,00050,000) • Most common symptomatic • Loss of B cell function • Mutations in genes associated with B-cell development (BAFFR, CD20, CD19, CD81, CD21, TACI, ICOS, LRBA, NFB) • Low Ig levels & inability to produce ab response • GI involvement is 9-20% • Chronic infections, autoimmune disease, granulomatous/ lymphocytic inflammation, malignancy • Infections: G. Lamblia, Campylobacter jejuni, Salmonella species, Microsporidia, Cryptosporidia CD3 CD38 stomach small intestine colon Histology Differential Dx Chronic atrophic gastritis ± IM Absence of plasma cells Autoimmune gastritis – Pernicious anemia HP gastritis Villous atrophy IELosis Nodular lymphoid hyperplasia GVHD-like features Neutrophilic infiltrate in LP Absence of plasma cells Granulomas Coeliac disease NHL GVHD Whipple’s disease Crohn’s disease Ulcers Cryptitis, Crypt abscesses Nodular lymphoid hyperplasia GVHD-like features Neutrophilic infiltrate in LP Absence of plasma cells Granulomas Crohn’s disease Ulcerative colitis Lymphocytic colitis Severe Combined Immunodeficiency (SCID) • 1 of 50,000 to 500,000 • Molecular defects in T-B-NK cell function • Presents first year of life with severe infections, rashes, failure to thrive, sepsis • Absence of T&NK cells,normal number-dysfunctional B cells • Mucosa with no organized lymphoid tissue • Opportunistic infections • Deficiencies in ADA, ZAP70, JAK3, IL2RG, JAK3, IL7RA, • GI biopsy shows hypocellular RAG1-2 and interleukin (IL)-7R lamina propria, without plasma cells & lymphocytes • X-linked form more common CD3 CD3 CD38 CD38 Chronic Granulomatous Disease (CGD) • 1 in 250 000 • GIT symptoms in 50-80% • X-linked common, others AR • Entire GIT • Mutations in NADPH • Most frequent in colon • Phagocytes unable to reduce O2 to create superoxide anion necessary to kill catalase+ mo • Chronic antigenic stimulation by mo - granuloma formation • Crohn’s-like colitis, proteinlosing enteropathy, gastric outlet obstruction • Biopsy shows granulomas, giant cells, pigmented macrophages CD68 Infections HIV/AIDS Acquired ID Immunosuppressive Tx Malnutrition RTx/ChTx Transplantation Stress Acquired Immunodeficiency Syndrome (AIDS) • Infection of CD4+ T lymphocytes by HIV • 50% present with GI symptoms • GIT site of replication & rich in mature T cells • All develop GI complications MucosalImmunology | VOLUME 1 NUMBER 1 | January 2008 1. HIV enteropathy 2. Opportunistic infections: rare after antibiotics 3. HIV-associated malignancies: Kaposi’s sarcoma and NHL (Burkitt’s and diffuse large B cell) HIV enteropathy • No infectious agent • Villous atrophy • Lymphocytic infiltration • Architectural distortion CD31 HHV8 Candidiasis, CMV, HSV, Kaposi’s sarcoma, idiopathic ulceration CMV, MAI, Kaposi’s sarcoma, NHL HIV enteropathy, MAI, Giardia, Isospora, Cryptosporidia, Strongyloides stercoralis, Kaposi’s sarcoma, NHL CMV, HSV, Clostridia, Salmonella, Shigella, Campylobacter, Cryptococcosis, Spirochetosis, Kaposi’s sarcoma, NHL Candida HSV CMV CMV Isospora CMV Stronglyloides Cryptococcus Schistosoma Cryptosporidium Microsporidium Graft versus Host Disease (GvHD) • Acute GvHD - 50% of allogeneic BM Txs • Upper GI> lower GI • GI, skin and/or liver • epithelial cell apoptosis + mild inflammation • Nonspecific GI symptoms • apoptosis in regenerative sites • Dx difficult in first 21 days basal crypt zone in intestines • Mimics: CMV, C. Difficile, bowel prep, AIDS neck cells in gastric mucosa Grade I Grade II Crypt cell apoptosis > crypt destruction and loss > mucosal sloughing Grade III Grade IV Chronic GvHD: >100 d after Tx • Ulcers and submucosal fibrosis in oesophagus-most commonly involved site • Mucosal and submucosal fibrosis in small intestine and crypt distortion in colon (IBD-like) •Gastric body and duodenal biopsies are highly sens & spec •Rectosigmoidoscopy > colonoscopy Take home messages • Dx of ID is difficult without clinical information • Clinical context is important • Histopathology is mostly nonspecific • Paucity of LP cells • Presence of mo • Mimics coeliac disease, IBD..
