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Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma

Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma Hindawi Case Reports in Immunology Volume 2021, Article ID 5574944, 8 pages https://doi.org/10.1155/2021/5574944 Case Report Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma 1 1 2 1 Tejal Narsai , Houfen Su , David Braxton , and Sudhir Gupta Division of Basic and Clinical Immunology, University of California, Irvine, California, USA Hoag Hospital, Newport Beach, California, USA Correspondence should be addressed to Sudhir Gupta; sgupta@uci.edu Received 4 February 2021; Accepted 14 May 2021; Published 26 May 2021 Academic Editor: Alessandro Plebani Copyright © 2021 Tejal Narsai et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. st Selective IgM deficiency (SIgMD) and isolated collagenous gastritis are two independent rare disorders. Our purpose is to report the 1 caseofSIgMDandisolatedcollagenousgastritisandcollagenousgastritisthathastransitionedtoEBV+gastricadenocarcinoma.Gastric biopsytissuewasanalyzedbyEBV-relatedencodedRNAinsituhybridizationassay.SubsetsofCD4,CD8,Tfollicularhelpercells(T ), FH andmembersofthe“regulatorylymphocytesclub”weremeasuredwithmultiplepanelsofmonoclonalantibodiesandisotypecontrolsby multicolor flow cytometry. )e patient was diagnosed with SIgMD (extremely low serum IgM 9mg/dl and normal IgG and IgA and exclusion of secondary causes of low IgM). Soon after SIgMD diagnosis, the patient developed collagenous gastritis and, 8 years later, developedgastricadenocarcinomathatwaspositiveforEBV.Anextensiveimmunologicalanalysisrevealedreducedna¨ıveCD4andCD8 effector memory T cells and increased naıve and central memory CD8 T cells. Among the circulating follicular helper T cells (cT ),T 1andT 2wereincreasedwhereasT 17wasdecreased.CD4TregcellsandT cellswereincreased,whereasBregandCD8 FH FH FH FH FR Treg were comparable to control. In conclusion, SIgMD may be associated with isolated collagenous gastritis, and collagenous gastritis may transition to EBV+gastric adenocarcinoma. A role of regulatory lymphocytes in gastric cancer is discussed. diffused disease including collagenous colitis [13]. Kamimura 1. Introduction etal.revieweddataonall60knowncasesofcollagenousgastritis SIgMD was first described in 1967 [1]; however, only re- reported until 2015, and no progression of collagenous gastritis cently has it been incorporated as a primary immunodefi- to gastric carcinoma was observed [14]. ciencyinIUISclassification[2].SIgMDis characterizedbya Collagenous gastritis has not been reported as a pre- serum IgM below 2 SD below the mean with normal serum disposing factor for gastric cancer, and collagenous gastritis IgG and IgA, and exclusion of secondary causes of low has not been reported in SIgMD. Furthermore, progression serum IgM [3]. Patients with SIgMD may be asymptomatic of collagenous gastritis to gastric adenocarcinoma has never or present with recurrent infections and allergic and/or been reported. autoimmune manifestations [4, 5]. A number of malignant Wepresent,tothebestofourknowledge,thefirstcaseof disorders have been reported in patients with SIgMD [6, 7]; SIgMD with isolated collagenous gastritis and transition of however, it is unclear whether there is a true increase in the collagenous gastritis to gastric adenocarcinoma. prevalence of malignancy in SIgMD. Collagenous gastroenteritis includes collagenous gastritis, 2. Materials and Methods collagenous sprue, and collagenous colitis and is characterized by subepithelial collagen deposition and infiltration by in- 2.1. Case Description. In 2017, a 53-year-old male was re- flammatory mononuclear cells in the lamina propria [8–12]. ferredtouswithahistoryofasthmaandallergicrhinitisand Among collagenous gastroenteritides, collagenous gastritis is history of recurrent upper respiratory tract infections. very rare and isolated collagenous gastritis is predominantly During his teenage years, he reported having frequent ep- present in children. In adults, it is generally associated with isodesofacutesinusitis.Inhis30s,hewasdiagnosedwithan 2 Case Reports in Immunology antibody was added to PBMCs for 30min. PBMCs were episode of meningitis, as well as multiple pneumonias. No further details were available regarding nature of infections. washed and fixed by 2% paraformaldehyde (PFA). For regulatory cells, the following surface staining cells Nopriorimmunologicalworkupwasperformed.Hisasthma was well controlled on inhaled corticosteroid therapy. His were fixed and permeablized by using a Foxp3 staining allergic rhinitis was well controlled with allergen immu- buffer set (BD Bioscience, San Jose, California) as per the notherapy and nasal fluticasone spray. An immunologic manufacturer’s protocol. Intracellular staining with anti- evaluation was performed. the patient had severely reduced Foxp3PE monoclonal antibody, and appropriate isotype IgM (9mg/dl; control 37–336) with normal IgG (698mg/dl; control (Mouse IgG1k-PE), was used for nonspecific control 660–1,660mg/dl) and IgA (145mg/dl; control staining. 80–400mg/dl) and normal response to pneumococcal Allflourescenceminusonecontrolsandisotypecontrols polysaccharide, diphtheria, and tetanus toxoid. CD3+, were stained and fixed by 2% PFA for flow cytometry. Cells were acquired by using the BD FACS Celesta (Becton- CD4+, CD8+, CD19+ B cells, and CD3-CD16+CD56+ NK cells were normal; secondary causes of low IgM were ex- Dickenson, San Jose, CA) equipped with a BVR laser. Forward and side scatters and singlets were used to gate and cluded. )erefore, a diagnosis of primary SIgMD was established. Since 2017, immunoglobulin levels were fre- exclude cellular debris. )irty thousand cells were acquired quently repeated on several occasions. Total IgG ranged and analyzed using FLOWJO software (Ashland, OR). between 698mg/dl–718mg/dl, and total IgM ranged be- )e following surface makers identified tween<9mg/dl and 17mg/dl. Soon after, he was evaluated various lymphocyte subsets: for epigastric burning and severe upper abdominal pain. An Subsets of CD4 T cells and CD8+ T cells: na¨ıve (TN)- endoscopywasperformed,andbiopsiesshowedcollagenous CD4+/CD8+CD45RA+CCR7+, central memory (TCM)- gastritis (Figure 1). He was started on twice daily proton CD4+/CD8+CD45RA-CCR7+, effector memory (TEM)- pump inhibitor and H2 blocker therapy, with relief of his CD4+/CD8+CD45RA-CCR7-, CD45RA+effector mem- symptoms. His gastritis was monitored with annual en- ory, and terminally differentiated effector memory doscopieswithrandombiopsies.Eightyearslater(2020),his (TEMRA)-CD4+/CD8+CD45RA+CCR7- screening endoscopy showed a new polyp that, on biopsy, Subsets of T follicular helper cells: cTFH-CD4+ revealed poorly differentiated gastric adenocarcinoma that CXCR5+CD45RA-, TFH1-CD4+CXCR5+CD45RA- was positive for EBV (Figure 2). Serum EBV-VCA IgM CCR6-CXCR3+, TFH2-CD4+CXCR5+CD45RA-CCR6- antibodies (U/ml)- undetected, EBV-VCA IgG antibodies CXCR3,TFH17-CD4+CXCR5+CD45RA-CCR6+CXCR3, (U/ml)-388 (control <22), EBNA-IgG antibodies (U/ml)- and TFH1+TFH17-CD4+CXCR5+CD45RA-CCR6+ 55.2 (control <22), EBV-EA diffuse antibodies (U/ml)-<5 CXCR3+ (control<11), and EBV-PCR-negative were found. He had no new symptoms. A PET CT was negative for metastatic Regulatory lymphocytes: CD4Treg–CD4+CD25+ lesion. He underwent total gastrectomy and had 0/22 pos- CD127- Foxp3+; CD8 Treg-CD8+CD183+ itive lymph nodes. No chemotherapy was instituted. He is CCR7+CD45RA-FoxP3+; TFR-CD4+CCR5+CD45RA- doing well clinically. CD25highFoxP3+; and Breg-CD19+CD24+CD38+ 3. Results 2.2. Sample Preparation. Peripheral blood was drawn from the patient following the diagnosis of gastric adenocarci- 3.1. Subsets of CD4 and CD8 T Cells. Naive T cells (T ) noma and from age- and gender-matched control. Pe- upon activation with an antigen undergo clonal expan- ripheral blood mononuclear cells (PBMCs) were isolated sion and differentiation to effector cells, and at the end of frombloodbyusingdensitygradientlymphocyteseparation immune response, they are retained as memory T cells. media. Human Subject Committee of theInstitution Review Based ontheirhomingproperties, expression ofadhesion Board of the University of California, Irvine, approved the molecules, and chemokine receptors, memory Tcells are protocol. Signed written consent was obtained. classified into central memory (T ) and effector CM memory (T ) CD4+ and CD8+ Tcells [15, 16]. A small EM population of T cells reacquire CD45RA and are EM 2.3. Antibodies and Reagents. )e following anti-human termed as terminally differentiated effector memory monoclonal antibodies and isotype controls were purchased T cells (T ). )ese subsets differ with regard to EMRA from BD Biosciences (San Jose, California): CD4 PerCP, proliferative response, cytokine production, effector CD8 PerCP, CD45RA APC, CCR7 FITC, CD183 PE, CD25 properties, and sensitivity to apoptosis [15]. )erefore, FITC, CD127 AL647, FoxP3 PE, CD278 (ICOS) AL647, we examined these subsets in our patient. CD4 T were CD183 BV421, CXCR5 AL488, PD1 APC, CD8 BV421, decreased, and CD4 T were increased (Figure 3(a)). CM CD45RA BV510, CD19 PerCP, CD38 FITC, and CD24 CD8 T and T increased, whereas T was decreased N CM EM FITC. (Figure 3(b)). 2.4. Flow Cytometry. Approximately 1 million PBMCs 3.2. Subsets of Follicular Helper T Cells. Circulating T cells FH were used per combination for antibody staining. 20 μl of (cT ) play an important role in germinal center formation, FH Case Reports in Immunology 3 (a) (b) Figure 1: (a) 4x magnification of the results of upper endoscopy biopsy showing nonspecific chronic inflammatory infiltrate with a thickened subepithelial collagen table. (b) 20x magnification higher-power image of the thickened subepithelial collagen table, showing diagnostic features of entrapped cellular elements such as inflammatory cells and blood vessels. (a) (b) (c) Figure 2: (a) 10x magnification of histopathology of the polypoid gastric body lesion showing poorly differentiated adenocarcinoma with surface ulceration. (b) High-power magnification of the gastric polypoid lesion showing high-grade dysplasia. (c) EBV-infected carcinoma cells (black stain present) juxtaposed with normal gastric glandular mucosa (black stain absent), using EBV-related encoded RNA in situ hybridization assay (EBER ish). immunoglobulin isotype switching, and differentiation of Collagenous infiltrative disorders of the gastrointestinal B cells to immunoglobulin-secreting cells [17, 18]. )e tract are characterized by subepithelial deposition of col- signaturecytokinetheyproduceisIL-21.However,basedon lagenbandswithmononuclearcellinfiltrationinthemucosa additional cytokines produced, cT has been further [25]. In 1989, Colleti and Trainer [26] reported the first case FH classified into T 1, T 2, and T 17 [19]. )erefore, we of collageneous gastritis in a 15-year-old girl who presented FH FH FH examinedallsubsetsofcT .cT ,T 1,andT 2,whereas with recurrent abdominal pain and bleeding. Collagenous FH FH FH FH T 17 was reduced as compared to control (Figure 4). gastritis is extremely rare; since 1989, less than 70 cases of FH collagenous gastritis have been reported. A few cases of collagenous gastroenteritis have been reported in primary 3.3. Regulatory Lymphocytes. )ere are 4 members of the immunodeficiency diseases [27–31]; however, isolated col- “regulatoryclub” [20–24].CD4Tregplaysanimportantrole lagenous gastritis has been reported only in one case of in immune tolerance and cancer [22]. In addition, T fol- hypogammaglobulinemia [32] and in one case of selective licular regulatory cells (T ) regulate the function of cT IgA deficiency [33]. Ours is the first case of collagenous FR FH cells [20, 21]. In addition, CD8 Treg and Breg have also been gastritis in SIgMD. )e pathogenesis of collagenous disor- shown to play a role in peripheral tolerance in cancer ders of the gastrointestinal tract remains unclear. A role of [23, 24]. )erefore, we examined all 4 theimmunesystemhasbeenproposedbasedoncollagenous regulatory lymphocytes. T cells and CD4 Treg were in- gastroenteritis in autoimmune diseases including systemic FR creased, whereas B reg and CD8 Treg were comparable to lupuserythematosus,Sjogren’ssyndrome,celiacdisease,and control (Figure 5). ulcerativecolitis [34–39]. Freeman reported celiacdisease in more than 20% of patients with collagenous colitis, a rate that exceeds the reported detection rates of celiac disease in 4. Discussion other clinical settings [40]. In a long-term follow-up of patients with collagenous SIgMD is a rare primary immunodeficiency disease char- gastritis ranging from 2–16 years, no case of gastric cancer acterizedbylowserumIgMandnormalIgGandIgA;Bcells has been observed [41, 42]. However, colon cancer has been with surface membrane IgM are normal [6]. We present the st rarely recorded in collagenous colitis [43]. Also intriguing 1 SIgMD patient who developed collagenous gastritis that was the coincidental later development of lymphomas in 2 transitioned to EBV+gastric adenocarcinoma. 4 Case Reports in Immunology 250K 200K 150K 3 100K 2 50K 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA 250K 200K 150K 3 100K 50K 10 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD45RA CD4 (a) 250 K 200 K 150 K Patient 100 K 2 50 K 1 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD8 CD45RA 250 K 200 K 150 K Control 100 K 2 50 K 1 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 CD8 CD45RA (b) Figure 3: (a) CD4 subsets: CD4+ subsets are characterized by different makers; na¨ıve (TN; CCR7+CD45RA+) central memory: TCM (CCR7+CD45RA-),effectormemory:TEM(CCR7-CD45RA-),TeffectormemoryRA:TEMRA(CCR7-CD45RA+).(b)CD8subset:CD8+ gated cells. In PBMCs, CD88+ T cells were gated and gated CD8+ cells subsets are characterized by different makers: TN (CCR7+ CD45RA+), TCM (CCR7+CD45RA-), TEM (CCR7-CD45RA-), and TEMRA (CCR7-CD45RA+). Abnormal values are circled in red. patients with collagenous colitis in the absence of celiac (HBV) and Helicobacter pylori (H. Pylori) have also been disease [40]. Previous reports have recorded Hodgkin and implicated in gastric cancer [49]. Kamimura et al. [42] non-Hodgkin lymphomas, including a mycosis fungoides- reviewed all 60 patients of collagenous gastritis reported in type T-cell lymphoma in collagenous colitis [44–46]. Ad- theworldliteratureuntil2015withafollow-uprangingfrom ditional studies will be needed to determine if there is an 2–14 years. )ey reported 6 adults and 4 children with collagenousgastritisthatwerepositivefor H. pylori.Noneof increased risk for these lymphoproliferative malignancies in collagenous colitis. the patients with collagenous gastritis have ever progressed Gastric cancer is the fourth most common cancer and to gastric cancer. Our patient was negative for H. pylori the second leading cause of death worldwide [47]. Gastric infection. In addition to H. pylori and EBV, other predis- cancer is the most common cause of death among CVID posing factorsfor gastriccancer includeatropicgastritisand patients[48].Epstein–Barrvirus(EBV)isdetectedin10%of pernicious anemia. Gastric malignancy has not been de- gastric adenocarcinoma patients [49–54]. Hepatitis B virus scribed in SIgMD. Gastric adenocarcinoma has been SSC SSC SSC SSC CCR7 CCR7 CCR7 CCR7 Case Reports in Immunology 5 Patient 250K 1 5 10 200K 4 10 0 1 2 3 4 5 10 10 10 10 10 10 150K CCR6 100K 2 50K 1 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA (a) Control 250 K 200 K 0 1 2 3 4 5 10 10 10 10 10 10 150 K 3 CCR6 100 K 2 50 K 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA (b) Figure 4: TFH cells: in PBMCs, CD4+ gated cells and various TFH subsets were characterized by different makers: cTFH- CXCR5+CD45RA- and TFH subsets TFH1 (CXCR3+CCR6-), THF1+THF17 (CXCR3+CCR6+), TFH2 (CXCR3-CCR6), and TFH17 (CXCR3-CCR6+). Abnormal values are circled in red. (a) CD4+T-cell subsets. (b) CD8+T-cell subsets. CD4 treg CD8 treg TFR Breg 5 5 5 5 5 10 10 10 10 10 4 4 4 4 4 10 10 10 10 10 3 3 3 3 3 10 10 10 10 10 Patient 2 2 2 2 2 10 10 10 10 10 1 1 1 1 1 10 10 10 10 10 0 0 0 0 0 10 10 10 10 10 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CD127 CD4 CD8 FoxP3 CD24 5 5 5 5 5 10 10 10 10 10 4 4 4 4 4 10 10 10 10 10 3 3 3 3 3 10 10 10 10 10 Control 2 2 2 2 2 10 10 10 10 10 1 1 1 1 1 10 10 10 10 10 0 0 0 0 0 10 10 10 10 10 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD8 FoxP3 CD24 CD127 Figure 5: Regulatory lymphocytes: CD4Treg gated CD4+ cells for CD25+CD127- and then analyzed as CD4+CD25+CD127-Foxp3+ cells. Abnormal values are circled in red. CD8 Treg: gated CCR7+CD25highCD45RA- CD8 Tcells expressing CD183 (CXCR3) and FoxP3. TFR cells were characterized as TFR-CD4+CCR5+CD45RA-CD25highFoxP3+ and Breg as CD19+CD24+CD38+. reportedinpatientswithotherprimaryimmunodeficiencies; prior to the development of EBV+adenocarcinoma. Fur- however, none were reported to be EBV+ [48, 55–62]. Our thermore, at the time of diagnosis, no EBV viremia was patient was diagnosed with collagenous gastritis eight years present. CD25 CD25 SSC SSC FoxP3 FoxP3 CXCR5 CXCR5 CXCR3 CXCR3 CD25 CD25 CXCR3 CXCR3 CD38 CD38 6 Case Reports in Immunology In order to understand a role of immune responses in References gastriccancerinourpatient,weexaminedvarioussubsetsof [1] J. R. Hobbs, R. D. Milner, and P. J. Watt, “Gamma-M defi- CD4+ and CD8+ Tcells and regulatory lymphocytes. Zhang ciency predisposing to meningococcal septicaemia,” BMJ, et al [63] reported increased TFH1 cells that promote in- vol. 4, no. 5579, pp. 583–586, 1967. flammation, suppress Breg, and correlatewith worse clinical [2] A. Bousfiha, L. Jeddane, C. 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Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma

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Copyright © 2021 Tejal Narsai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Immunology Volume 2021, Article ID 5574944, 8 pages https://doi.org/10.1155/2021/5574944 Case Report Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma 1 1 2 1 Tejal Narsai , Houfen Su , David Braxton , and Sudhir Gupta Division of Basic and Clinical Immunology, University of California, Irvine, California, USA Hoag Hospital, Newport Beach, California, USA Correspondence should be addressed to Sudhir Gupta; sgupta@uci.edu Received 4 February 2021; Accepted 14 May 2021; Published 26 May 2021 Academic Editor: Alessandro Plebani Copyright © 2021 Tejal Narsai et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. st Selective IgM deficiency (SIgMD) and isolated collagenous gastritis are two independent rare disorders. Our purpose is to report the 1 caseofSIgMDandisolatedcollagenousgastritisandcollagenousgastritisthathastransitionedtoEBV+gastricadenocarcinoma.Gastric biopsytissuewasanalyzedbyEBV-relatedencodedRNAinsituhybridizationassay.SubsetsofCD4,CD8,Tfollicularhelpercells(T ), FH andmembersofthe“regulatorylymphocytesclub”weremeasuredwithmultiplepanelsofmonoclonalantibodiesandisotypecontrolsby multicolor flow cytometry. )e patient was diagnosed with SIgMD (extremely low serum IgM 9mg/dl and normal IgG and IgA and exclusion of secondary causes of low IgM). Soon after SIgMD diagnosis, the patient developed collagenous gastritis and, 8 years later, developedgastricadenocarcinomathatwaspositiveforEBV.Anextensiveimmunologicalanalysisrevealedreducedna¨ıveCD4andCD8 effector memory T cells and increased naıve and central memory CD8 T cells. Among the circulating follicular helper T cells (cT ),T 1andT 2wereincreasedwhereasT 17wasdecreased.CD4TregcellsandT cellswereincreased,whereasBregandCD8 FH FH FH FH FR Treg were comparable to control. In conclusion, SIgMD may be associated with isolated collagenous gastritis, and collagenous gastritis may transition to EBV+gastric adenocarcinoma. A role of regulatory lymphocytes in gastric cancer is discussed. diffused disease including collagenous colitis [13]. Kamimura 1. Introduction etal.revieweddataonall60knowncasesofcollagenousgastritis SIgMD was first described in 1967 [1]; however, only re- reported until 2015, and no progression of collagenous gastritis cently has it been incorporated as a primary immunodefi- to gastric carcinoma was observed [14]. ciencyinIUISclassification[2].SIgMDis characterizedbya Collagenous gastritis has not been reported as a pre- serum IgM below 2 SD below the mean with normal serum disposing factor for gastric cancer, and collagenous gastritis IgG and IgA, and exclusion of secondary causes of low has not been reported in SIgMD. Furthermore, progression serum IgM [3]. Patients with SIgMD may be asymptomatic of collagenous gastritis to gastric adenocarcinoma has never or present with recurrent infections and allergic and/or been reported. autoimmune manifestations [4, 5]. A number of malignant Wepresent,tothebestofourknowledge,thefirstcaseof disorders have been reported in patients with SIgMD [6, 7]; SIgMD with isolated collagenous gastritis and transition of however, it is unclear whether there is a true increase in the collagenous gastritis to gastric adenocarcinoma. prevalence of malignancy in SIgMD. Collagenous gastroenteritis includes collagenous gastritis, 2. Materials and Methods collagenous sprue, and collagenous colitis and is characterized by subepithelial collagen deposition and infiltration by in- 2.1. Case Description. In 2017, a 53-year-old male was re- flammatory mononuclear cells in the lamina propria [8–12]. ferredtouswithahistoryofasthmaandallergicrhinitisand Among collagenous gastroenteritides, collagenous gastritis is history of recurrent upper respiratory tract infections. very rare and isolated collagenous gastritis is predominantly During his teenage years, he reported having frequent ep- present in children. In adults, it is generally associated with isodesofacutesinusitis.Inhis30s,hewasdiagnosedwithan 2 Case Reports in Immunology antibody was added to PBMCs for 30min. PBMCs were episode of meningitis, as well as multiple pneumonias. No further details were available regarding nature of infections. washed and fixed by 2% paraformaldehyde (PFA). For regulatory cells, the following surface staining cells Nopriorimmunologicalworkupwasperformed.Hisasthma was well controlled on inhaled corticosteroid therapy. His were fixed and permeablized by using a Foxp3 staining allergic rhinitis was well controlled with allergen immu- buffer set (BD Bioscience, San Jose, California) as per the notherapy and nasal fluticasone spray. An immunologic manufacturer’s protocol. Intracellular staining with anti- evaluation was performed. the patient had severely reduced Foxp3PE monoclonal antibody, and appropriate isotype IgM (9mg/dl; control 37–336) with normal IgG (698mg/dl; control (Mouse IgG1k-PE), was used for nonspecific control 660–1,660mg/dl) and IgA (145mg/dl; control staining. 80–400mg/dl) and normal response to pneumococcal Allflourescenceminusonecontrolsandisotypecontrols polysaccharide, diphtheria, and tetanus toxoid. CD3+, were stained and fixed by 2% PFA for flow cytometry. Cells were acquired by using the BD FACS Celesta (Becton- CD4+, CD8+, CD19+ B cells, and CD3-CD16+CD56+ NK cells were normal; secondary causes of low IgM were ex- Dickenson, San Jose, CA) equipped with a BVR laser. Forward and side scatters and singlets were used to gate and cluded. )erefore, a diagnosis of primary SIgMD was established. Since 2017, immunoglobulin levels were fre- exclude cellular debris. )irty thousand cells were acquired quently repeated on several occasions. Total IgG ranged and analyzed using FLOWJO software (Ashland, OR). between 698mg/dl–718mg/dl, and total IgM ranged be- )e following surface makers identified tween<9mg/dl and 17mg/dl. Soon after, he was evaluated various lymphocyte subsets: for epigastric burning and severe upper abdominal pain. An Subsets of CD4 T cells and CD8+ T cells: na¨ıve (TN)- endoscopywasperformed,andbiopsiesshowedcollagenous CD4+/CD8+CD45RA+CCR7+, central memory (TCM)- gastritis (Figure 1). He was started on twice daily proton CD4+/CD8+CD45RA-CCR7+, effector memory (TEM)- pump inhibitor and H2 blocker therapy, with relief of his CD4+/CD8+CD45RA-CCR7-, CD45RA+effector mem- symptoms. His gastritis was monitored with annual en- ory, and terminally differentiated effector memory doscopieswithrandombiopsies.Eightyearslater(2020),his (TEMRA)-CD4+/CD8+CD45RA+CCR7- screening endoscopy showed a new polyp that, on biopsy, Subsets of T follicular helper cells: cTFH-CD4+ revealed poorly differentiated gastric adenocarcinoma that CXCR5+CD45RA-, TFH1-CD4+CXCR5+CD45RA- was positive for EBV (Figure 2). Serum EBV-VCA IgM CCR6-CXCR3+, TFH2-CD4+CXCR5+CD45RA-CCR6- antibodies (U/ml)- undetected, EBV-VCA IgG antibodies CXCR3,TFH17-CD4+CXCR5+CD45RA-CCR6+CXCR3, (U/ml)-388 (control <22), EBNA-IgG antibodies (U/ml)- and TFH1+TFH17-CD4+CXCR5+CD45RA-CCR6+ 55.2 (control <22), EBV-EA diffuse antibodies (U/ml)-<5 CXCR3+ (control<11), and EBV-PCR-negative were found. He had no new symptoms. A PET CT was negative for metastatic Regulatory lymphocytes: CD4Treg–CD4+CD25+ lesion. He underwent total gastrectomy and had 0/22 pos- CD127- Foxp3+; CD8 Treg-CD8+CD183+ itive lymph nodes. No chemotherapy was instituted. He is CCR7+CD45RA-FoxP3+; TFR-CD4+CCR5+CD45RA- doing well clinically. CD25highFoxP3+; and Breg-CD19+CD24+CD38+ 3. Results 2.2. Sample Preparation. Peripheral blood was drawn from the patient following the diagnosis of gastric adenocarci- 3.1. Subsets of CD4 and CD8 T Cells. Naive T cells (T ) noma and from age- and gender-matched control. Pe- upon activation with an antigen undergo clonal expan- ripheral blood mononuclear cells (PBMCs) were isolated sion and differentiation to effector cells, and at the end of frombloodbyusingdensitygradientlymphocyteseparation immune response, they are retained as memory T cells. media. Human Subject Committee of theInstitution Review Based ontheirhomingproperties, expression ofadhesion Board of the University of California, Irvine, approved the molecules, and chemokine receptors, memory Tcells are protocol. Signed written consent was obtained. classified into central memory (T ) and effector CM memory (T ) CD4+ and CD8+ Tcells [15, 16]. A small EM population of T cells reacquire CD45RA and are EM 2.3. Antibodies and Reagents. )e following anti-human termed as terminally differentiated effector memory monoclonal antibodies and isotype controls were purchased T cells (T ). )ese subsets differ with regard to EMRA from BD Biosciences (San Jose, California): CD4 PerCP, proliferative response, cytokine production, effector CD8 PerCP, CD45RA APC, CCR7 FITC, CD183 PE, CD25 properties, and sensitivity to apoptosis [15]. )erefore, FITC, CD127 AL647, FoxP3 PE, CD278 (ICOS) AL647, we examined these subsets in our patient. CD4 T were CD183 BV421, CXCR5 AL488, PD1 APC, CD8 BV421, decreased, and CD4 T were increased (Figure 3(a)). CM CD45RA BV510, CD19 PerCP, CD38 FITC, and CD24 CD8 T and T increased, whereas T was decreased N CM EM FITC. (Figure 3(b)). 2.4. Flow Cytometry. Approximately 1 million PBMCs 3.2. Subsets of Follicular Helper T Cells. Circulating T cells FH were used per combination for antibody staining. 20 μl of (cT ) play an important role in germinal center formation, FH Case Reports in Immunology 3 (a) (b) Figure 1: (a) 4x magnification of the results of upper endoscopy biopsy showing nonspecific chronic inflammatory infiltrate with a thickened subepithelial collagen table. (b) 20x magnification higher-power image of the thickened subepithelial collagen table, showing diagnostic features of entrapped cellular elements such as inflammatory cells and blood vessels. (a) (b) (c) Figure 2: (a) 10x magnification of histopathology of the polypoid gastric body lesion showing poorly differentiated adenocarcinoma with surface ulceration. (b) High-power magnification of the gastric polypoid lesion showing high-grade dysplasia. (c) EBV-infected carcinoma cells (black stain present) juxtaposed with normal gastric glandular mucosa (black stain absent), using EBV-related encoded RNA in situ hybridization assay (EBER ish). immunoglobulin isotype switching, and differentiation of Collagenous infiltrative disorders of the gastrointestinal B cells to immunoglobulin-secreting cells [17, 18]. )e tract are characterized by subepithelial deposition of col- signaturecytokinetheyproduceisIL-21.However,basedon lagenbandswithmononuclearcellinfiltrationinthemucosa additional cytokines produced, cT has been further [25]. In 1989, Colleti and Trainer [26] reported the first case FH classified into T 1, T 2, and T 17 [19]. )erefore, we of collageneous gastritis in a 15-year-old girl who presented FH FH FH examinedallsubsetsofcT .cT ,T 1,andT 2,whereas with recurrent abdominal pain and bleeding. Collagenous FH FH FH FH T 17 was reduced as compared to control (Figure 4). gastritis is extremely rare; since 1989, less than 70 cases of FH collagenous gastritis have been reported. A few cases of collagenous gastroenteritis have been reported in primary 3.3. Regulatory Lymphocytes. )ere are 4 members of the immunodeficiency diseases [27–31]; however, isolated col- “regulatoryclub” [20–24].CD4Tregplaysanimportantrole lagenous gastritis has been reported only in one case of in immune tolerance and cancer [22]. In addition, T fol- hypogammaglobulinemia [32] and in one case of selective licular regulatory cells (T ) regulate the function of cT IgA deficiency [33]. Ours is the first case of collagenous FR FH cells [20, 21]. In addition, CD8 Treg and Breg have also been gastritis in SIgMD. )e pathogenesis of collagenous disor- shown to play a role in peripheral tolerance in cancer ders of the gastrointestinal tract remains unclear. A role of [23, 24]. )erefore, we examined all 4 theimmunesystemhasbeenproposedbasedoncollagenous regulatory lymphocytes. T cells and CD4 Treg were in- gastroenteritis in autoimmune diseases including systemic FR creased, whereas B reg and CD8 Treg were comparable to lupuserythematosus,Sjogren’ssyndrome,celiacdisease,and control (Figure 5). ulcerativecolitis [34–39]. Freeman reported celiacdisease in more than 20% of patients with collagenous colitis, a rate that exceeds the reported detection rates of celiac disease in 4. Discussion other clinical settings [40]. In a long-term follow-up of patients with collagenous SIgMD is a rare primary immunodeficiency disease char- gastritis ranging from 2–16 years, no case of gastric cancer acterizedbylowserumIgMandnormalIgGandIgA;Bcells has been observed [41, 42]. However, colon cancer has been with surface membrane IgM are normal [6]. We present the st rarely recorded in collagenous colitis [43]. Also intriguing 1 SIgMD patient who developed collagenous gastritis that was the coincidental later development of lymphomas in 2 transitioned to EBV+gastric adenocarcinoma. 4 Case Reports in Immunology 250K 200K 150K 3 100K 2 50K 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA 250K 200K 150K 3 100K 50K 10 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD45RA CD4 (a) 250 K 200 K 150 K Patient 100 K 2 50 K 1 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD8 CD45RA 250 K 200 K 150 K Control 100 K 2 50 K 1 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 CD8 CD45RA (b) Figure 3: (a) CD4 subsets: CD4+ subsets are characterized by different makers; na¨ıve (TN; CCR7+CD45RA+) central memory: TCM (CCR7+CD45RA-),effectormemory:TEM(CCR7-CD45RA-),TeffectormemoryRA:TEMRA(CCR7-CD45RA+).(b)CD8subset:CD8+ gated cells. In PBMCs, CD88+ T cells were gated and gated CD8+ cells subsets are characterized by different makers: TN (CCR7+ CD45RA+), TCM (CCR7+CD45RA-), TEM (CCR7-CD45RA-), and TEMRA (CCR7-CD45RA+). Abnormal values are circled in red. patients with collagenous colitis in the absence of celiac (HBV) and Helicobacter pylori (H. Pylori) have also been disease [40]. Previous reports have recorded Hodgkin and implicated in gastric cancer [49]. Kamimura et al. [42] non-Hodgkin lymphomas, including a mycosis fungoides- reviewed all 60 patients of collagenous gastritis reported in type T-cell lymphoma in collagenous colitis [44–46]. Ad- theworldliteratureuntil2015withafollow-uprangingfrom ditional studies will be needed to determine if there is an 2–14 years. )ey reported 6 adults and 4 children with collagenousgastritisthatwerepositivefor H. pylori.Noneof increased risk for these lymphoproliferative malignancies in collagenous colitis. the patients with collagenous gastritis have ever progressed Gastric cancer is the fourth most common cancer and to gastric cancer. Our patient was negative for H. pylori the second leading cause of death worldwide [47]. Gastric infection. In addition to H. pylori and EBV, other predis- cancer is the most common cause of death among CVID posing factorsfor gastriccancer includeatropicgastritisand patients[48].Epstein–Barrvirus(EBV)isdetectedin10%of pernicious anemia. Gastric malignancy has not been de- gastric adenocarcinoma patients [49–54]. Hepatitis B virus scribed in SIgMD. Gastric adenocarcinoma has been SSC SSC SSC SSC CCR7 CCR7 CCR7 CCR7 Case Reports in Immunology 5 Patient 250K 1 5 10 200K 4 10 0 1 2 3 4 5 10 10 10 10 10 10 150K CCR6 100K 2 50K 1 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA (a) Control 250 K 200 K 0 1 2 3 4 5 10 10 10 10 10 10 150 K 3 CCR6 100 K 2 50 K 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD45RA (b) Figure 4: TFH cells: in PBMCs, CD4+ gated cells and various TFH subsets were characterized by different makers: cTFH- CXCR5+CD45RA- and TFH subsets TFH1 (CXCR3+CCR6-), THF1+THF17 (CXCR3+CCR6+), TFH2 (CXCR3-CCR6), and TFH17 (CXCR3-CCR6+). Abnormal values are circled in red. (a) CD4+T-cell subsets. (b) CD8+T-cell subsets. CD4 treg CD8 treg TFR Breg 5 5 5 5 5 10 10 10 10 10 4 4 4 4 4 10 10 10 10 10 3 3 3 3 3 10 10 10 10 10 Patient 2 2 2 2 2 10 10 10 10 10 1 1 1 1 1 10 10 10 10 10 0 0 0 0 0 10 10 10 10 10 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CD127 CD4 CD8 FoxP3 CD24 5 5 5 5 5 10 10 10 10 10 4 4 4 4 4 10 10 10 10 10 3 3 3 3 3 10 10 10 10 10 Control 2 2 2 2 2 10 10 10 10 10 1 1 1 1 1 10 10 10 10 10 0 0 0 0 0 10 10 10 10 10 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 1 2 3 4 5 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CD4 CD8 FoxP3 CD24 CD127 Figure 5: Regulatory lymphocytes: CD4Treg gated CD4+ cells for CD25+CD127- and then analyzed as CD4+CD25+CD127-Foxp3+ cells. Abnormal values are circled in red. CD8 Treg: gated CCR7+CD25highCD45RA- CD8 Tcells expressing CD183 (CXCR3) and FoxP3. TFR cells were characterized as TFR-CD4+CCR5+CD45RA-CD25highFoxP3+ and Breg as CD19+CD24+CD38+. reportedinpatientswithotherprimaryimmunodeficiencies; prior to the development of EBV+adenocarcinoma. Fur- however, none were reported to be EBV+ [48, 55–62]. Our thermore, at the time of diagnosis, no EBV viremia was patient was diagnosed with collagenous gastritis eight years present. CD25 CD25 SSC SSC FoxP3 FoxP3 CXCR5 CXCR5 CXCR3 CXCR3 CD25 CD25 CXCR3 CXCR3 CD38 CD38 6 Case Reports in Immunology In order to understand a role of immune responses in References gastriccancerinourpatient,weexaminedvarioussubsetsof [1] J. R. Hobbs, R. D. Milner, and P. J. Watt, “Gamma-M defi- CD4+ and CD8+ Tcells and regulatory lymphocytes. Zhang ciency predisposing to meningococcal septicaemia,” BMJ, et al [63] reported increased TFH1 cells that promote in- vol. 4, no. 5579, pp. 583–586, 1967. flammation, suppress Breg, and correlatewith worse clinical [2] A. Bousfiha, L. Jeddane, C. 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Case Reports in ImmunologyHindawi Publishing Corporation

Published: May 26, 2021

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