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Year : 2021  |  Volume : 1  |  Issue : 3  |  Page : 179-181

Novel heterozygous mutation of CIITA gene presenting with recurrent infections and systemic lupus erythematosus

1 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, Puducherry
2 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, Puducherry

Date of Submission24-May-2021
Date of Decision27-Jul-2021
Date of Acceptance08-Aug-2021
Date of Web Publication31-Aug-2021

Correspondence Address:
Dr. Jaikumar Govindaswamy Ramamoorthy
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_150_21

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Background: The expression of major histocompatibility complex (MHC) molecule is essential for homeostasis of the immune system. The expression of MHC-II is regulated by the master regulator for transcription, the Class II transactivator (CIITA) gene. Homozygous mutations affecting the CIITA gene result in bare lymphocyte syndrome type-II, but the clinical manifestations of heterozygous mutations are not well reported. Clinical Description: Herein, we describe the roller coaster course of a 6-year-old child who had presented with recurrent infections in infancy and systemic lupus erythematosus (SLE) in toddler age, who was later found to have heterozygous mutation in the CIITA gene. Management: The child was managed with immunosuppression for SLE and monthly intravenous immunoglobulin replacement therapy and daily cotrimoxazole prophylaxis for features of immunodeficiency. Conclusion: This case report aims to provide more insight into the clinical features associated with heterozygous mutations of CIITA.

Keywords: Autoimmune, bare lymphocyte syndrome, immunodeficiency, major histocompatibility complex, systemic lupus erythematosus

How to cite this article:
Chidambaram AC, Ramamoorthy JG, Krishnamurthy S, Manivannan P, Karunakar P. Novel heterozygous mutation of CIITA gene presenting with recurrent infections and systemic lupus erythematosus. Indian Pediatr Case Rep 2021;1:179-81

How to cite this URL:
Chidambaram AC, Ramamoorthy JG, Krishnamurthy S, Manivannan P, Karunakar P. Novel heterozygous mutation of CIITA gene presenting with recurrent infections and systemic lupus erythematosus. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 26];1:179-81. Available from: http://www.ipcares.org/text.asp?2021/1/3/179/325083

The expression of major histocompatibility complex (MHC) molecule is essential for homeostasis of the immune system. Tissue-specific expression of MHC-II is regulated at the level of transcription. Four transacting genes control and coordinate the MHC-II expression are Class II transactivator (CIITA), RFX5, RFXANK, and RFXAP.[1] The master regulator for transcription of the MHC-II gene is CIITA. Homozygous mutations in any of these four genes result in bare lymphocyte syndrome type-II, a rare genetic disorder characterized by a lack of expression of MHC-II antigens, which lead to a combined immunodeficiency disorder.[2] However, manifestations of heterozygous mutations of these genes have not been well described.

We present this case to highlight the presenting features of heterozygous mutation of CIITA gene in a toddler where he presents with features of immunodeficiency and systemic lupus erythematosus (SLE).

  Clinical Description Top

Our index child was the sixth-order child born to a third-degree consanguineous couple with a birth weight of 3 kg. The family history was significant in the form of two female siblings who succumbed to severe sepsis and meningitis before 1 year of age. A male sibling had a history of recurrent episodes of severe anemia requiring blood transfusion since the age of 18 months and finally succumbed by 2 years of age. The index child presented to us at 15 months of age with complaints of fever, respiratory distress, reduced activity, and feeding for 3 days, suggestive of lower respiratory tract infection. He had a stormy infantile period with recurrent episodes of lower respiratory tract infection, persistent diarrhea, and failure to thrive since the age of 9 months, necessitating multiple hospitalization and intravenous injections. None of the signature organisms pertaining to immunodeficiency could be isolated during the evaluation of these episodes. His weight at 15 months was 7.5 kg (−3.05 Z), length was 74 cm (−2.41 Z), and weight for length was −3.29 Z, suggesting severe acute malnutrition. The child was febrile (101°f) and tachypneic (54 breaths/min) with normal perfusion and saturation on 4 L/min oxygen supplementation being 97%. General examination revealed mild pallor without any evidence of jaundice, lymphadenopathy, cyanosis, clubbing, or edema without evidence for any micronutrient deficiency. Respiratory examination revealed normal breath sounds and diffuse bilateral crepitations. His systemic examination was unremarkable. Laboratory reports did not reveal any lymphopenia, thrombocytopenia, or neutropenia. The liver and renal function tests, evaluation for tuberculosis and human immunodeficiency virus, repeated bacterial cultures of blood, urine, and stool samples, stool evaluation for parasitic infestation, and chest roentgenogram were all unremarkable. The duodenal and colonic biopsies were planned in view of persistent diarrhea and failure to thrive which revealed features consistent with eosinophilic enteritis.

The child presented again at 4 years of age with severe pallor (hemoglobin 3.6 g/l), failure to thrive, hepatosplenomegaly, and congestive cardiac failure. His mother reported intermitted episodes of persistent diarrhea and bronchopneumonia in the last 3 years, which were managed conservatively by his primary care physician.

  Management and Outcome Top

Evaluation for immunodeficiency disorders was performed at 18 months of age. Lymphocyte subset analysis by flow cytometry revealed: absolute lymphocyte count - 2700/μl, CD4 cells - 12% (322/μl; reference range 1900–2900 μl), CD8 cells - 43% (1154 μl; reference range 667–1473/μl), B cells - 7% (188/μl; reference range 160–370/μl), NK cells - 14% (376/μl; reference range - 50–4000/μl). Serum immunoglobulin evaluation by nephelometry showed: IgG - 18.6 g/l (reference range 5.33–13.78 g/l), IgM - 1.01 g/l (reference range 0.28–2.18 g/l), IgA - <0.246 g/l (reference range 0.24–1.01 g/l), and IgE - <4.4 IU/ml. Thus, the CD4 cell count and serum immunoglobulin A levels were reduced for his age. A possibility of combined immunodeficiency was considered. However, further functional and genetic evaluation for immunodeficiency could not be performed as the child was lost to follow-up.

On next presentation at 4 years of age, he had spherocytosis with reticulocytosis, hemoglobinuria, decreased serum haptoglobulin, and elevated lactate dehydrogenase, suggestive of intravascular hemolysis with positive direct Coomb's test. The child also had stage-I hypertension and proteinuria (1+) with low serum C3 levels (42 mg/dl). Hence, a possibility of SLE was entertained and worked up. Serum antinuclear antibody and anti-double-stranded DNA were positive (4+). However, the serum albumin (3.3 g/dl), serum cholesterol (122 mg/dl), serum creatinine (0.53 mg/dl), blood urea (39 mg/dl), aspartate transaminases (23 IU/l), and alanine transaminases (28 IU/l) were within normal limits. Renal biopsy showed evidence of class-II lupus nephritis. He did not have other systemic manifestations of SLE such as cutaneous features, arthritis, neurological changes, serositis, and antiphospholipid antibodies. The presence of absence of cutaneous and neurological manifestations excluded complement deficiency-induced lupus as our differential diagnosis. European League Against Rheumatism/American College of Rheumatology 2019 criteria[3] to diagnose SLE were fulfilled (score = 25; score ≥10 classifies SLE with 96% sensitivity and 93% specificity). The child was treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone and mycophenolate mofetil for 4 weeks. Laboratory evaluation (complete hemogram and urine analysis) after 4 weeks confirmed that the child was under remission. The dose of prednisolone was tapered gradually and mycophenolate mofetil was continued with oral hydroxychloroquine.

During the 3rd month of the steroid taper, there was an isolated hematological flare of SLE (hemoglobin - 3.3 g/l). For this isolated hematological flare, he was treated with intravenous methylprednisolone pulses and 4 weekly doses of injection rituximab. Mycophenolate mofetil maintenance was continued, and he remains in a state of clinical remission status till now.

Since the index child had presented with features of combined immunodeficiency disorder initially and features of SLE later, further evaluation was done to identify the immunodeficiency disorder. Clinical-exome sequencing by next generation sequencing testing revealed a heterozygous missense variation in exon 13 of the CIITA gene, resulting in the amino acid substitution of leucine for valine at codon 94. Although this mutation is not described previously in literature, the in silico prediction of the variant was damaging by SIFT and mutation tester. Quantitative activity of MHC-II molecules can be assessed by human leukocyte antigen (HLA)-DR expression on monocytes, and qualitative activity of MHC-II molecules can be assessed by antibody response to vaccines. Flow cytometric evaluation for HLA-DR expression on monocytes was performed. It was observed that 87% of the monocytes expressed HLA-DR antigen [Figure 1]a and [Figure 1]b, dismissing a quantitative defect. Antibody titer to vaccination revealed a deficiency of antibodies against tetanus toxoid after 6 weeks of immunization that confirmed a qualitative defect in the MHC-II molecule. The child was initiated on monthly intravenous immunoglobulin replacement therapy, and daily cotrimoxazole prophylaxis for the past 1 year as a bridge till stem cell transplantation is performed.
Figure 1: (a) Peripheral flow cytometry - CD14-gated monocytes - 87% express human leukocyte antigen-DR. (b) Peripheral flow cytometry - CD64-gated monocytes - 84% express human leukocyte antigen-DR

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  Discussion Top

The CIITA gene encodes a protein called the MHC-II transactivator. Homozygous mutations in this gene result in bare lymphocyte syndrome which severely cripples the immune system and leads to a combined immunodeficiency disorder. The CIITA is considered as a transcriptional coactivator as it does not directly bind to DNA. It exerts its function through the activation of transcription factor RFX5. The CIITA protein acts as a positive regulator of MHC-II complex gene transcription and is therefore referred to as the master control factor for the expression of these genes. Our case adds insight to the clinical manifestations of heterozygous CIITA gene mutation. Functional activity of MHC-II molecule is very vital in antigen presentation functioning and T cell and B cell interaction. This child had most of the features of MHC-II deficiency - failure to thrive, recurrent respiratory tract infections, protracted diarrhea, hypogammaglobulinemia, and CD4 lymphopenia due to defective T and B cell functioning. There have been reports of cases with recurrent infections secondary to heterozygous mutation of one of the four transacting regulators of MHC-II expression.[4] All of these cases lacked expression of HLA-DR on monocytes. These cases highlight the quantitative defect of MHC-II protein due to CIITA mutation. In addition, CIITA gene is also responsible for the qualitative function of MHC-II.[5] A single amino acid deletion has been reported to be sufficient to abolish the activity of CIITA in vivo.[6] The HLA-DR expression was normal in our patient, which confirms the quantitative presence of MHC-II. Presence of low antibody titer to vaccine response could probably be due to poor T and B cell interaction, resulting in poor antibody response to subunit protein vaccines. This makes us speculate these immunodeficiency manifestations in our index child as secondary to CIITA mutation. However, animal model studies with functional assays were not done to confirm the same. Autoimmune cytopenias have been described in cases with heterozygous mutations of CIITA, but features of SLE have not been reported so far.[7] The presence of MHC-II is paramount for central tolerance in preventing the development of autoreactivity. Three mechanisms have been described to silence the development of autoreactive cells at the first checkpoint in bone marrow - deletion, anergy, and receptor editing.[8] All these factors together could have triggered SLE in this patient.[9] This has been emphasized by the fact that CIITA mutation has been identified as one of the susceptible genes for SLE by genome-wide association studies.[10]

Most children with homozygous mutation of the CIITA gene succumbed to underlying infection by 5 years of age without bone marrow transplantation.[2] Since our index child managed to survive till 5 years without bone marrow transplant, we hypothesize that the heterozygous mutations, though significant to cause immunodeficiency, may be less lethal.

To conclude, homozygous mutations of CIITA have been well known to cause primary immunodeficiency. However, heterozygous mutation causing clinically significant immunodeficiency is less reported. In this case, a novel presentation of primary immunodeficiency with autoimmunity adds a new facet to existing literature.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Shrestha D, Szöllosi J, Jenei A. Bare lymphocyte syndrome: An opportunity to discover our immune system. Immunol Lett 2012;141:147-57.  Back to cited text no. 1
Griscelli C. Combined immunodeficiency with defective expression in major histocompatibility complex Class II genes. Clin Immunol Immunopathol 1991;61:S106-10.  Back to cited text no. 2
Aringer M. EULAR/ACR classification criteria for SLE. Semin Arthritis Rheum 2019;49:S14-7.  Back to cited text no. 3
Doll R, McGarry D, Jhaveri D, et al. Heterozygous mutations of the major histocompatibility Class-II associated molecules. Ann Allergy Asthma Immunol 2018;121:S100-1.  Back to cited text no. 4
Reith W, LeibundGut-Landmann S, Waldburger JM. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol 2005;5:793-806.  Back to cited text no. 5
Dziembowska M, Fondaneche MC, Vedrenne J, et al. Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics 2002;53:821-9.  Back to cited text no. 6
Rigg L, Sanan N, Jhaveri D, et al. Two novel mutations of major histocompatibility Class-II associated molecules. J Clin Immunol 2019;39:1.  Back to cited text no. 7
Duraes FV, Thelemann C, Sarter K, et al. Role of major histocompatibility complex Class II expression by non-hematopoietic cells in autoimmune and inflammatory disorders: Facts and fiction. Tissue Antigens 2013;82:1-15.  Back to cited text no. 8
Waldburger JM, Masternak K, Muhlethaler-Mottet A, et al. Lessons from the bare lymphocyte syndrome: Molecular mechanisms regulating MHC Class II expression. Immunol Rev 2000;178:148-65.  Back to cited text no. 9
Delmonte OM, Schuetz C, Notarangelo LD. RAG deficiency: Two genes, many diseases. J Clin Immunol 2018;38:646-55.  Back to cited text no. 10


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