IMMUNOLOGY CORNER


https://doi.org/10.5005/jp-journals-10081-1374
Pediatric Infectious Disease
Volume 4 | Issue 4 | Year 2022

Autoimmunity and Inborn Errors of Immunity: Two Faces of the Same Coin!


Neha Singh1, Sagar Bhattad2

1,2Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Aster CMI Hospital, Bengaluru, Karnataka, India

Corresponding Author: Sagar Bhattad, Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Aster CMI Hospital, Bengaluru, Karnataka, India, Phone: +91 9779433934, e-mail: drsagarbhattad@gmail.com

Received on: 13 June 2022; Accepted on: 05 September 2022; Published on: 31 December 2022

ABSTRACT

Autoimmune disorders are a heterogeneous group of disorders characterized by immune dysregulation and are associated with a loss of tolerance to self-antigens. Autoimmunity in patients with inborn errors of immunity (IEI) has always been a puzzling phenomenon! Autoimmunity may be the first clinical presentation or sequel in patients with IEI. In this paper, we discuss the mechanisms of autoimmunity in IEI and present a few clinical cases highlighting the need to consider an IEI in patients presenting with autoimmunity and infections, polyautoimmunity, and polyendocrinopathy.

How to cite this article: Singh N, Bhattad S. Autoimmunity and Inborn Errors of Immunity: Two Faces of the Same Coin! Pediatr Inf Dis 2022;4(4):153-155.

Source of support: Nil

Conflict of interest: None

Keywords: Autoimmunity, Immune deficiency, Immune dysregulation.

INTRODUCTION

Autoimmune disorders are a heterogeneous group of disorders characterized by immune dysregulation and are associated with a loss of tolerance to self-antigens. Autoimmunity in patients with IEI has always been a puzzling phenomenon! However, with a better understanding of the immune development pathways, it is observed that IEIs and autoimmunity are interlinked by common mechanisms.1

Autoimmunity may be the first clinical presentation or sequel in patients with IEI. The expanding spectrum of IEIs now includes diseases with autoimmunity, which have been classified as “syndromes with autoimmunity” by the International Union of Immunological Societies Expert Committee on IEI in 2019.2

When should one suspect an IEI in a patient with autoimmunity?

Pathogenesis of Autoimmunity in IEI

The pathophysiology of different autoimmune manifestations in IEIs is complex and has been associated with decreased central and peripheral tolerance, with the presence of autoreactive T and B cells. Some of the proposed mechanisms are:

  • Defective clearance of autoreactive T cells: AIRE gene mutations are associated with impaired clearance of autoreactive T cells in the thymus, as well as affecting the development of T regulatory (Treg) cells. The associated conditions are autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and Omenn syndrome. RAG 1/RAG 2 genes are crucial for the rearrangement of T and B cell receptors by facilitating variable (V) diversity (D) joining (J) recombination. The mutations in these genes hinder the negative selection of autoreactive T cells in the thymus. The leakage of autoreactive T cells may provide the link between infections and autoimmunity in patients with RAG defects.

  • Infection and autoimmunity: Patients with IEI are unable to clear infections effectively. The molecular mimicry of the pathogen with human tissues leads to autoreactivity, and the cellular debris which is presented to autoreactive T cells triggers the autoimmune cascade, known as “bystander activation.” Also, infections with organisms like Staphylococcus and Mycoplasma produce superantigens which result in nonspecific polyclonal activation of T cells and cytokine production.

  • Defects in Treg development: T regulatory cells are a subset of T cells that play an important role in tolerance and prevent autoimmunity. The defects in the development of Treg cells are associated with loss of inflammatory control and result in autoimmunity. This has been reported in patients with APECED who have low forkhead box protein P3 (FOXP3), which is important for Treg cell activation and development. Other IEIs associated with autoimmunity and low Treg cells are immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), CD25 deficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome, CTLA4 deficiency, LRBA deficiency, STAT3 GOF mutations, BACH2 deficiency, CD122 deficiency, DEF6 deficiency, and FERMT1 deficiency (Table 1).

Table 1: Errors of immunity which present with autoimmunity as a key feature
Inborn IEI Associated gene
CTLA-4 haploinsufficiency CTLA-4
LRBA deficiency LRBA
Autoimmune lymphoproliferative syndrome TNFRSF6
APECED AIRE
IPEX FOXP3
STAT3 GOF mutation STAT3
Very-early onset IBD IL-10, IL-10R

Let us discuss a few cases.

CASE 1

A 6-year-old boy born to a non-consanguineously married Indian couple presented with chronic diarrhea for over a year. He had lost 4 kg weight over 1 year.

Past history: He was noted to have blood in stools at 4 years of age and had a history of recurrent episodes of wheeze-associated lower respiratory tract infections as a young boy.

Family history: He had a significant family history. His father, a 35-year-old gentleman, had a history of autoimmune hemolytic anemia (AIHA) since the age of 15 years. He was suffering from chronic diarrhea, which was responsive to steroids. His paternal grandmother, a 55-year-old lady, had three relapses of AIHA. Interestingly, she too was suffering from chronic diarrhea, which was found to be responsive to steroids (autoimmune enteropathy) (Fig. 1).

Fig. 1: Pedigree

On evaluation:

CBC—hemoglobin (Hb): 9 gm/dL, total count (TC): 10200/mm3, and platelet count (PC): 340000/mm3.

Coombs test: Negative.

Immunoglobulin (Ig) levels, lymphocyte subset analysis: Normal.

Nitroblue tetrazolium and dihydrorhodamine assay: Normal.

Fecal calprotectin levels: 1220 µg/gm (high).

Colon biopsy: Features suggestive of inflammatory bowel disease (IBD).

Genetic test: Pathogenic heterozygous mutation in CTLA4 gene in the child, father, and paternal grandmother.

Diagnosis: CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI).

CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI)

Message: Autoimmunity in multiple family members—one must evaluate for IEI.

CASE 2

A 4-year-old girl presented with a history of malar rash, oral ulcers, and alopecia for 1 year. She also had a history of recurrent otitis media from a young age and one episode of meningitis at 3 years of age.

On examination: She had ulcers over the hard palate and erythematous malar rash (butterfly rash).

On evaluation:

Genetic test: Pathogenic homozygous mutation in the C1QA gene.

Diagnosis: Monogenic lupus—C1q deficiency.

C1q deficiency

Message: Early onset lupus (<5 years) with recurrent infections—one must think of IEI.

CASE 3

A 40-year-old lady with a history of recurrent pneumonia from a young age now presented with polyarthritis for 1 year.

On examination: She had generalized wasting and bilateral crepitations on auscultation. She had arthritis involving small joints of the hands and both knees.

On evaluation:

Genetic test: Negative.

Diagnosis: Common variable immunodeficiency with inflammatory arthritis.

Treatment: She was treated with a course of steroids, after which arthritis became passive. She is on monthly immunoglobulin (IVIG) replacement.

Common variable immunodeficiency

CASE 4

A 7-year-old girl presented with complaints of chronic diarrhea for 3 months. In the past, she had several episodes of lower respiratory infections and recurrent oral thrush. She also had autoimmune thyroiditis, diagnosed at 5 years of age, and was being treated with thyroxine.

On examination: Onychomycosis affecting multiple nails and bilateral coarse crepitations.

On evaluation:

Genetic test: Pathogenic heterozygous variant in STAT1 gene.

Diagnosis: STAT1 gain of function (AD) with chronic mucocutaneous candidiasis and autoimmune thyroiditis.

STAT1 gain of function mutation

Message: Endocrinopathy with recurrent infections—think of IEI.

CONCLUSION

REFERENCES

1. Amaya-Uribe L, Rojas M, Azizi G, et al. Primary immunodeficiency and autoimmunity: a comprehensive review. J Autoimmun 2019;99:52–72. DOI: 10.1016/j.jaut.2019.01.011

2. Bousfiha A, Jeddane L, Picard C, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol 2020;40(1):66–81. DOI: 10.1007/s10875-020-00758-x

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