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Monogenic inborn errors of immunity in autoimmune disorders

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Abstract

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases (AID), the study included 56 subjects (male:female ratio: 1.07) with mean age of onset of autoimmunity 7 years (4 months–46 years). 21/56 had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > gastrointestinal (GI) (16%) > skin (14%) > endocrine (10%) > rheumatological (8%) > renal (6%) > neurological (2%). 36/56 reported recurrent infections. 27/56 were on polyimmunotherapy. 18/52 (35%) had CD19 lymphopenia, 24/52 (46%) had CD4 lymphopenia, 11/52 (21%) had CD8 lymphopenia, and 14/48 (29%) had NK lymphopenia. 21/50 (42%) had hypogammaglobinemia; 3 of whom were given rituximab. 28/56 were found to have pathogenic variants among PIRD genes. These 28 patients had 42 AID among which hematological was most common (50%) > GI (14%) = skin (14%)> endocrine (9%) > rheumatological (7%) > renal and neurological (2%). Hematological AID was the most common AID (75%) in children with PIRD. Positive predictive value (PPV) of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD and sensitivity of 17%. Polyautoimmunity had a PPV of 35% and sensitivity of 40%. 11/28 of these children were offered transplant. 8/28 were started on sirolimus, 2/28 on abatacept, and 3/28 on baricitinib/ruxolitinib after diagnosis. In conclusion, 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests, and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.

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Abbreviations

AID:

Autoimmune disease

JMF:

Jeffrey Modell Foundation

PID:

Primary immunodeficiency

PIRD:

Primary immune regulatory disorders

IEI:

Inborn errors of immunity

LRBA:

Lipopolysaccharide (LPS)-responsive and beige-like anchor protein deficiency

STAT1/3 GOF:

Signal transducer and activator of transcription 1/3 gain of function

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency

ACP5:

Acid phosphatase 5

NFKB1/2:

Nuclear factor NF-kappa-B subunit 1/2

NLRP12:

NACHT, LRR, and PYD domains-containing protein 12

CARD11 GOF:

Caspase recruitment domain family member 11

RTEL1:

Regulator of telomere elongation helicase 1

NCF2:

Neutrophil cytosolic factor 2

ATM:

Ataxia-telangiectasia mutated

RAG1:

Recombination activating gene 1

BTK:

Bruton tyrosine kinase

IL12RB1:

Interleukin 12 receptor beta subunit 1

CHAPEL:

Hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy

FOXP3:

Forkhead box P3

PIK3CD:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

CD40L:

Cluster of differentiation 40 ligand

ADA2:

Adenosine deaminase 2 deficiency

PCR:

Polymerase chain reaction

EBV:

Epstein-Barr virus

CMV:

Cytomegalovirus

ANA:

Anti-nuclear antibody

GAD:

Glutamic acid decarboxylase

TTgIgA:

Tissue transglutaminase immunoglobulin A

DCT:

Direct Coombs test

TPO:

Thyroid peroxidase

CBC:

Complete blood count

TNFAIP3:

Tumor necrosis factor, alpha-induced protein 3

DNASE1:

Deoxyribonuclease I

MEFV:

MEditerranean FeVer

IL2RB:

Interleukin-2 receptor subunit beta

LYST:

Lysosomal trafficking regulator

ERCC6:

ERCC excision repair 6, chromatin remodeling factor

PRF1:

Perforin 1

SUMO4:

Small ubiquitin like modifier 4

VUS:

Variant of uncertain significance

GI:

Gastrointestinal

JAK:

Janus kinase

CMC:

Chronic mucocutaneous candidiasis

VEOIBD:

Very early onset inflammatory bowel disease

DM:

Diabetes mellitus

HBA1C:

Hemoglobin A1c

HSCT:

Hematopoietic stem cell transplant

CVID:

Common variable immunodeficiency

IVIG:

Intravenous immunoglobulin

ACMG:

American College of Medical Genetics

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Acknowledgements

We would like to acknowledge Dr. Zinet Currimbhoy who started the immunology department at B. J. Wadia Hospital for Children in early 2000s and continued to support and mentor the department till her death in 2021. Dr. Sangeeta Mudaliar, Dr. Purva Kanvinde, Dr. Ritika Khurana, Dr. Ira Shah, Dr. Sudha Rao, Dr. Rajesh Joshi, Dr. Sikha Agarwal, Dr. Manish Shah, Dr. Alpana Ohri, Dr. Laxmi Shobhavat, Dr. Rekha Solomon, Dr. Shilpa Kulkarni, and Dr. Ambreen Pandrowala from Bai Jerbai Wadia hospital for children for patient referral and management.

Funding

The study was partly funded by Indian Council of Medical Research (ICMR), New Delhi, India, under the Centre of Excellence in PID project (vide Grant No. 61/02/2012/IMM/BMS).

Author information

Authors and Affiliations

  1. Department of Immunology, Bai Jerbai Wadia Hospital for Children, Acharya Dhonde Marg, Parel, Mumbai, 400012, India

    Iyengar Vaishnavi Venkatachari, Akshaya Chougule, Vijaya Gowri, Prasad Taur, Minnie Bodhanwala, Shakuntala Prabhu & Mukesh Desai

  2. National Institute of Immunohematology, ICMR, KEM, Parel, Mumbai, India

    Manisha Madkaikar

Authors
  1. Iyengar Vaishnavi Venkatachari
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  2. Akshaya Chougule
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  3. Vijaya Gowri
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  4. Prasad Taur
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  5. Minnie Bodhanwala
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  6. Shakuntala Prabhu
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  7. Manisha Madkaikar
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  8. Mukesh Desai
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Contributions

Vaishnavi V Iyengar conceptualized and designed the study, collection and analysis of data, drafted the initial manuscript, reviewed and revised the manuscript. Akshaya Chougule collected data, reviewed and revised the manuscript. Vijaya Gowri collected data, carried out the initial analysis, reviewed and revised the manuscript. Prasad Taur collection of data, carried out the initial analysis, reviewed and revised the manuscript. Shakuntala Prabhu and Minnie Bodhanwala supervised data collection and critical revision of article. Manisha Madkaikar immunological work-up of patient, reviewed and revised the manuscript. Mukesh M Desai conceptualized the study, supervision of study, interpretation of data and critical revision of article.

Corresponding author

Correspondence to Mukesh Desai.

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Ethics approval was taken from our hospital ethics committee. Helsinki declaration was followed.

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A written informed consent was taken from the guardian of the child included in the study.

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The authors declare no competing interests.

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Venkatachari, I.V., Chougule, A., Gowri, V. et al. Monogenic inborn errors of immunity in autoimmune disorders. Immunol Res 71, 771–780 (2023). https://doi.org/10.1007/s12026-023-09391-3

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