Posted on Authorea 18 Jun 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159248830.04720089 | This a preprint and has not been peer reviewed. Data may be preliminary. euao o rncito fteMCI eei IT.Hmzgu uain ffcigteCIAgene CIITA the affecting master The Homozygous the . CIITA. of type-II of is syndrome level homeostasis the for MHC-II bare at in essential the regulated results of is is transcription molecule MHC-II for of (MHC) regulator expression Complex Tissue-specific Histocompatibility system. Major immune of expression The Abstract 2 Figures: presented had who child age. Nil 5-year-old toddler insight Tables: in a more (SLE) provide report erythematosus We to lupus CIITA. The aims systemic of report type-II. and mutations case the syndrome infancy heterozygous this in of lymphocyte Hence, with transcription bare recurrent associated for in reported. with system. features regulator well results immune master clinical not gene the are The the CIITA mutations of into the transcription. heterozygous homeostasis affecting of of mutations for level manifestations Homozygous essential the clinical CIITA. at is is regulated molecule gene is (MHC) MHC-II MHC-II Complex of Histocompatibility expression Tissue-specific Major of expression The Abstract 2020 18, June 3 2 1 Manivannan Prabhu Chidambaram Chandran Aakash and infections erythematosus recurrent lupus with Systemic presenting gene CIITA heterozygous of novel to secondary system immune Dysregulated aaallIsiueo otrdaeMdclEuainadRsac (JIPMER) Research and Education Medical Postgraduate Education of Medical Institute Graduate Jawaharlal Research Post and of Education Institute Medical Jawaharlal Postgraduate of Institute Jawaharlal N niula Antinuclear Syndrome Lymphocyte Bare Sequencing Generation Next Antigen Leukocyte Human ANA Immunodeficiency Variable Virus Common BLS Immunodeficiency Human Rheumatology of NGS College Rheumatism/American Assay Against Immunosorbant erythematosus League European HLA Linked lupus Enzyme Systemic EULAR/ACR Complex Histocompatibility Major CVID HIV ELISA SLE MHC Abbreviations 1 n eiel Karunakar Pediredla and , 1 akmrRamamoorthy Jaikumar , 1 h lnclmnfsain fhtrzgu uain r not are mutations heterozygous of manifestations clinical The . 1 1 2 rrmKrishnamurthy Sriram , 3 , Posted on Authorea 18 Jun 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159248830.04720089 — This a preprint and has not been peer reviewed. Data may be preliminary. ue fSEltr ute vlainwsdn oietf h muoecec iodr lwcytometric Flow disorder. fea- immunodeficiency and the initially identify disorder to done immunodeficiency was combined evaluation of further clinical features later, with in SLE presented was of had He tures child The months. index the 6 (350mg/m nephritis. Since next Rituximab active the period. injection this for of of during continued suggestive status were doses remission features hydroxychloroquine weekly pulses and any 4 methylprednisolone mofetil, intravenous reveal and with 3.3gm/L). mycophenolate not initiated (hemoglobin- days was SLE did 3 Treatment of negative. analysis flare for were hematological urine a was DNA and there anti-ds tapered tests taper, was steroid function prednisolone the of Renal of dose month hydroxychloroquine. The third oral the remission. with During under continued was was intravenous child mofetil the mycophenolate with that oral and treated confirmed gradually with weeks was (2mg/kg/day) 4 prednisolone child after oral The analysis) by (925mg/m followed excluded diagnose days mofetil (score=25). to 3 manifestations mycophenolate satisfied for criteria neurological were (30mg/kg/dose) 2019 and pulse EULAR/ACR (SLE) cutaneous methylprednisolone diagnosis. erythematosus of with antiphospholipid differential lupus absence hypertension domain, our systemic of The serositis as view man- lupus domain, negative. systemic in deficiency-induced neurological other all complement (done arthritis, have were biopsy not domain, domains did Renal cutaneous He mg/dL) antibody i.e (0.53 nephritis. limits. SLE lupus creatinine normal of class-II serum within ifestations of mg/dL), were evidence (122 showed mg/dL) (4+ proteinuria) cholesterol and (39 sub-nephrotic positive entertained serum was were urea (3.3g/dL), SLE (dsDNA) blood albumin of DNA severe serum and possibility anti-double-stranded of a the and view Hence, However, (ANA) mg/dL). in antibody ). (42 antinuclear diagnosed levels Serum initially C3 was up. serum worked low syndrome hemolysis with Evans (1+) intravascular IgG. proteinuria of for and hyperbilirubine- positive suggestive indirect was (9000/ features and managed test count thrombocytopenia were were Coomb’s reticulocyte congestive which There Direct elevated and years, hemoglobinuria, three mia). inter- gm/L) smear, physician. last reported peripheral 3.6 care the mother in (hemoglobin in primary His (spherocytes pallor bronchopneumonia hepatosplenomegaly. his severe and and by with thrive conservatively persistent to age of failure of episodes significant years was mitted four There follow-up. at failure. to again cardiac lost was presented child child immunodefi- the for The as evaluation or performed further immunodeficiency be However, combined not of considered. could possibility was ciency A (CVID) negative. Immunodeficiency was Variable IgA- ELISA Common 1.01g/L, (HIV) virus IgM- immunodeficiency g/L, of Human IgG-18.6 months 2700/ showed: 18 count- < nephelometry at lymphocyte by absolute performed evaluation was revealed: immunoglobulin cytometry disorders flow (322/ immunodeficiency upper by cells-12% through for analysis T performed Evaluation subset biopsy was colonic Lymphocyte biopsy The duodenal results. age. a be enteritis. similar thrive, eosinophilic could to revealed with immunodeficiency failure consistent thrombocytope- also to for features lymphopenia, pertaining workup revealed organomegaly, stormy of which organisms no endoscopy, a part was failure signature gastrointestinal with As There and the age neutropenia. of episodes. diarrhea of or these None months persistent nia of sibling 15 months , evaluation age. at male 18 the tract of us A of during respiratory months to isolated age lower presented 9 age. the child of since of since index thrive episodes year transfusion The to recurrent 1 blood age. with before requiring of of period years anemia meningitis weight 2 infantile severe birth and by of a sepsis succumbed with episodes severe finally couple recurrent and to consanguineous of succumbed third-degree history siblings a a to female had Two born child kg. sixth-order a 3 was child index Our age. infections with recurrent toddler associated with in Description presented features (SLE) Case had clinical erythematosus who the lupus child into systemic 5-year-old insight and more a infancy provide report in We to CIITA. aims of report mutations case heterozygous this Hence, reported. well . Um.Tu,tehle elcutadsrmimngoui eeswr eue o i age. his for reduced were levels A immunoglobulin serum and count cell T helper the Thus, IU/mL. 4.4 μ ) yooi el-3 (1154 cells-43% T cytotoxic L), μ )adatimn eoyi nma h hl lohdsaeIhypertension stage-I had also child The anemia. hemolytic autoimmune and L) 2 o ek.Lbrtr vlain(opeehmga n urine and hemogram (complete evaluation Laboratory weeks. 4 for ) μ ) el-%(188/ cells-7% B L), 2 2 .Tprn oeo rlprednisolone, oral of dose Tapering ). μ ) Kcls1%(376/ cells-14% NK L), < .4gL IgE- 0.246g/L, μ μ ) Serum L). ,helper L, Posted on Authorea 18 Jun 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159248830.04720089 — This a preprint and has not been peer reviewed. Data may be preliminary. rzgu uaincuigciial infiatimndfiinyi esrpre.I hscs,anovel a het- literature. case, But existing this to In facet immunodeficiency. new interest: primary a reported. of adds cause Conflict less autoimmunity to is with immunodeficiency known immunodeficiency primary significant well of clinically presentation been causing have mutation CIITA erozygous of mutations Homozygous immun- cause to significant Conclusion though years mutations, 5 heterozygous lethal. by less that infection maybe hypothesize underlying odeficiency, we to transplant, succumbed marrow transplantation gene marrow bone CIITA studies bone the without association of age genome-wide mutation of by homozygous SLE with could for children together Most factors susceptible these the All of tolerance. one patient central as this and prominent identified in more anergy been of defective SLE have to would triggered presentation mechanisms leading have selection selection poor thereby negative unusual patients, Alternate to of these BLS. failure bone leads with in patients the in function in to present checkpoint leads MHC be first This to Defective the cells. T-cells epithelial at self-reactive editing. thymic of cells receptor medullary auto-reactive to and antigens developing anergy, tissue-restricted features silence deletion, but to - CIITA, described far of marrow so mutations been reported heterozygous have a with been was mechanisms not cases which have in expression, SLE However, described HLA-DR of been stimulated have . IFN[?] cytopenias MHC-II an Autoimmune defective perform functionally our not case. causing could our in in we manifestations mutation, limitation limitations, immunodeficiency CIITA resource these to to hypothesize secondary due we are Thus, child MHC-II. index of vivo presence responsible in quantitative also CIITA is the of gene activity CIITA MHC-II Additionally, the of mutation. abolish function CIITA infections, qualitative to MHC-II tract the due of protein child for regulators respiratory MHC-II transacting This recurrent four of the defect thrive, quantitative of mutation. with to one cases of gene of failure mutation reports CIITA expression heterozygous deficiency- been to have heterozygous MHC-II secondary There of infections lymphopenia. of recurrent CD4 manifestations and features clinical , the diarrhea, the protracted of to most insight had adds described. case well been Our not genetic have antigens rare a genes MHC-II type-II, of these RFXAP. Syndrome expression of RFXANK, Lymphocyte of mutations Bare RFX5, lack in a CIITA, result by genes expression- characterized four MHC-II disorder these of the any coordinate in mutations and Homozygous control genes a transacting as Four year one past the for performed. Discussion prophylaxis is transplantation acyclovir cell and immunoglob- stem cotrimoxazole Intravenous till monthly daily bridge on , initiated human replacement was child (IVIG) 91 The ulin release an- ENST00000324288.8). Ensemble Gene (p.val954Leu; the 94 indication. codon against clinical program a the VEP revealed to (chr16:g.11004088G using testing relevant NGS performed were were Sentieon- The was that obtained analyzed. variants model. variants and sequences the Generation identify aligner The Sentieon of to Next the used notation by platform. using been (GRCh37/hg19) sequencing sequencing genome has Whole-exome the Illumina reference haplotype-caller of 1B). human the 87% the and using to 1A performed performed. aligned was was (Fig. monocytes (NGS) antigen on Sequencing expression HLA-DR (HLA)-DR expressed Antigen monocytes Leucocyte Human for evaluation 3,4 l fteecsslce xrsino L-Ro ooye.Teecsshglgtthe highlight cases These monocytes. on HLA-DR of expression lacked cases these of All . 8 h D el hthv sae h omlslcinpoeshv enobserved been have process selection normal the escaped have that cells T CD4 The . > h uhr elr htte aen oflc finterest. of conflict no have they that declare authors The ;Depth:73x) C; 9 hshsbe mhszdb h atta IT uainhsbeen has mutation CIITA that fact the by emphasized been has This . eeoyosmses aito neo 3o h IT gene CIITA the of 13 exon in variation missense heterozygous 6 7 h L-Repeso a omli u ain,wihconfirms which patient, our in normal was expression HLA-DR The . h rsneo H-Ii aaon o eta oeac.Three tolerance. central for paramount is MHC-II of presence The . 5 igeaioai eeinhsbe eotdt esffiin to sufficient be to reported been has deletion acid amino single A . eutn nteaioai usiuino ecn o aieat Valine for Leucine of substitution acid amino the in resulting 2 ic u ne hl aae osrietl er without years 5 till survive to managed child index our Since . 3 2 oee,mnfsain fheterozygous of manifestations However, . 10 . Posted on Authorea 18 Jun 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159248830.04720089 — This a preprint and has not been peer reviewed. Data may be preliminary. emneO cut ,NtrneoL A ecec:ToGns ayDsae.Junlo Clinical of Journal Diseases. Many Genes, Two Deficiency: RAG L. 2018;38(6):646-655 Notarangelo Immunology. C, Immunological from Schuetz Lessons expression. O, II al. Delmonte class et MHC S regulating Landmann mechanisms M, 2000;178(1):148-165. molecular Peretti Reviews. J, syndrome: facts Villard histocompatibility lymphocyte A, disorders: bare major Muhlethaler-Mottet the inflammatory of K, and Role Masternak autoimmune W. J, Waldburger in Reith 2013;82(1):1-15 cells S, Antigens. non-hematopoietic Hugues Tissue by H, fiction. expression Acha-Orbea and II K, Class-II Sarter class Histocompatibility C, complex Major 1 of Thelemann 1): Mutations F, 2019;39(Suppl II- Novel Immunology. Duraes Two class Clinical H. of MHC Tcheurekdjian Journal in D, Molecules. Jhaveri gene Associated N, CIITA Sanan 2002;53(10-11):821-829. the L, Immunogenetics. of Rigg immunodeficiency. the mutations severe by novel a expression with Three patients gene M. deficient II Fondanech class Marie-Claude MHC Dziembowska, of Regulation class JM. MHC transactivator. Waldburger to II due S, class syndrome LeibundGut-Landmann 2005;115(2):S83 lymphocyte W, ClinicalImmunology. Atypicalbare Reith and A. Allergy Irani of W, Journal Zhao insufficiency. C, II Koenig D, Mitchell DeMuthK, THE & OF MUTATIONS Asthma HETEROZYGOUS Allergy, H. of 2018;121(5):S100-S101 Tcheurekdjian Annals Immunology. R, MOLECULES. ASSOCIATED Hostoffer CLASS-II D, HISTOCOMPATIBILITY Jhaveri MAJOR D, McGarry R, class Doll complex histocompatibility major in expression genes. defective II with immunodeficiency Combined C. Griscelli tem. Sz D, Shrestha HLA-DR express 84% monocytes- gated References CD64 HLA-DR - express cytometry 87% flow monocytes- Peripheral gated 1B- -CD14 cytometry flow Peripheral 1A- Figure figures for Legends muo Lett Immunol lnImnlImmunopathol Immunol Clin l˝ s ,JniA aelmhct ydoe nopruiyt icvrorimn sys- immune our discover to opportunity An syndrome: lymphocyte Bare A. Jenei ¨ oll˝osi J, 2012;141(2):147-157. . a e Immunol Rev Nat 1991;61(2):S106-S110 . 2005: 5 793–806. : 4 Posted on Authorea 18 Jun 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159248830.04720089 — This a preprint and has not been peer reviewed. Data may be preliminary. 5 Posted on Authorea 18 Jun 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159248830.04720089 — This a preprint and has not been peer reviewed. Data may be preliminary. 6