First Association of Interleukin 12 Receptor Beta 1 Deficiency with Sjögren’s Syndrome

Abstract

IntroductionInterleukin 12 receptor beta 1 (IL12Rβ1) deficiency is a primary immunodeficiency resulting mainly in susceptibility to opportunistic infection by non-tuberculous, environmental mycobacteria and severe infection caused by Salmonella spp. Till now, less than 300 patients with IL12Rβ1 deficiency have been reported. Among them, only three have been described to develop autoimmunity.Case presentationWe present the case of a 50-year-old male with IL12Rβ1 deficiency due to compound heterozygosity [c. 1623_1624delGCinsTT (pGln542Stop) and c.1791 + 2T > C (donor splice site)], who—18 months after diagnosis of disseminated BCGitis—presented with recurrent fever and sicca syndrome. No indication of an infectious origin of these symptoms could be found at that point. The diagnosis of a Sjögren’s syndrome (SS) was made on the basis of fulfilled American-European consensus classification criteria, including a positive minor salivary gland biopsy.ConclusionApart from persistent antigenic stimulation, which may drive autoimmune inflammation in primary immunodeficiency, evidence on the involvement of interleukin 12 in pathogenesis of SS suggests that the same immunological mechanism may underlie both defense against infection and the maintenance of tolerance. To our knowledge, this is the first report of a case of autoimmunity in the form of SS in a patient with a primary immunodeficiency and one of the rare cases of IL12Rβ1 deficiency with manifested autoimmunity.

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

“…Seven new IL12RB1 mutations were identified: four large deletions (Δ1-7, Δ8, Δ12, and Δ15-17), one large duplication (dup10-12), one indel (c.747_752delinsAAAAT), and one missense mutation (p.R212Q). The other two mutations (p.R521* and c.1791+2T>G) identified here have been described before [2, 3, 8, 15, 16, 22, 28–34]. In the five kindreds, IL-12Rβ1 deficiency was caused by a CNV (deletion or duplication) in the homozygous state or in compound heterozygosity with a nonsense mutation, missense mutation, small indel, or splice-site mutation.…”

“…In kindred D, we identified a splice-site mutation in P4 affecting the donor flanking splice site of exon 15 (c.1791+2T>G), which seemed to be homozygous. This mutation is the most frequently reported mutation of IL12RB1 [2, 3, 8, 15, 16, 22, 28–34]. However, coverage between intron 14 and the 3′ region in P4 was also half that for a healthy control, suggesting a heterozygous deletion encompassing exons 15 to 17 and overlapping the c.1791+2T>G mutation (Figure 2A).…”

“…These small mutations invariably cause a complete lack of IL-12Rβ1 expression. Some of these mutations are recurrent: a founder effect, dating back 475 years, has been characterized for the c.1623_1624delinsTT mutation, which has been reported in 18 kindreds from eight countries, all of European descent [15, 22, 25–27] whereas a hotspot is suspected for the c.1791+2T>G mutation [21], which has been reported in 18 kindreds from 11 countries on four continents (Africa, America, Asia, and Europe) [2, 3, 8, 16, 22, 28–34]. …”

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

Autoantibodies in patients with interleukin 12 receptor beta 1 deficiency

“…In IL‐12Rβ1 deficiency, the evidence of a correlation with autoimmune phenomena is lacking. Only a few case reports have been described in terms of its association with Sjögren's syndrome (SS), systemic lupus erythematosus and hemolytic anemia …”