Mikko Seppänen

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

The evolution of cellular deficiency in GATA2 mutation

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

Subtly Impaired Humoral Immunity Predisposes to Frequently Recurring Genital Herpes Simplex Virus Type 2 Infection and Herpetic Neuralgia

BACKGROUND Immunogenetic factors predisposing to recurrent genital herpes remain poorly characterized. METHODS In a prospective case-control study, 52 consecutive patients with frequently recurring outbreaks of genital herpes were compared with 80 herpes simplex virus (HSV)-seropositive (types 1 and 2) and 70 HSV-seronegative control subjects. Immunoglobulins (Igs), type-specific anti-HSV-2 IgG and IgG subclass antibodies against glycoprotein G, levels of C3 and C4, and classical pathway hemolytic complement activity were measured, and IgG1 and IgG3 allotyping; C4 immunophenotyping; C4* real-time polymerase chain reaction (PCR) genotyping; and HLA-A*, B*, and DR* typing were performed. RESULTS The G3m(g),G1m(a/a(x)) haplotype was more frequent in patients than in HSV-seronegative control subjects (P=.047). Compared with all control subjects, low levels of total IgG1 (odds ratio [OR], 4.9 [95% confidence interval {CI}, 2.0-12.5]; P=.001) and IgG3 (OR 3.6 [95% CI 1.7-7.8]; P=.001), but not of anti-HSV-2 antibodies, were associated with recurrences. Levels of complement were lowest in patients. The C4* null type was negatively associated with neuralgia (OR, 0.2 [95% CI, 0.06-0.81]; P=.022). CONCLUSIONS Low levels of antibody-dependent cellular cytotoxicity-mediating IgG1 and IgG3 antibodies, partly dependent of allotype, may predispose to recurrent genital herpes. Antibodies produced by T helper type 1 responses, potentially against an unknown epitope, appear to be relevant in recurrences. In patients, C4* deficiencies are associated with protection from herpetic neuralgias, possibly through reduced inflammation.

Immunoglobulins and complement factor C4 in adult rhinosinusitis

We assessed whether complement and its factor C4 or abnormal immunoglobulin levels are associated with chronic or recurrent rhinosinusitis. We used multiple patient and control groups to obtain clinically meaningful data. Adult chronic or recurrent rhinosinusitis and acute purulent rhinosinusitis patients were compared with unselected adults and controls without previous rhinosinusitis. Associated clinical factors were reviewed. Levels of immunoglobulins, plasma C3, C4 and classical pathway haemolytic activity were analysed. C4 immunophenotyping was used to detect C4A and C4B deficiencies as null alleles. Complement was up‐regulated in rhinosinusitis. C4A nulls and low IgA, IgG, IgG1, IgG2, IgG3 and IgG4 levels were all more common in chronic or recurrent rhinosinusitis patients than in unselected and healthy controls. We searched for relevant differences between the patient groups. According to stepwise logistic regression analysis, nasal polyposis [odds ratio (OR) 10·64, 95% confidence interval (CI) 2·5–45·7, P = 0·001], bronchial asthma (OR 8.87, 95% CI 2·3–34·9, P = 0·002), C4A null alleles (OR 5·84, 95% CI 1·4–24·9, P = 0·017) and low levels of IgG4 together with either IgG1 or IgG2 (OR 15·25, 95% CI 1·4–166·8, P = 0·026) were more common in chronic or recurrent rhinosinusitis than in acute rhinosinusitis patients. Isolated low IgG subclasses had limited value in patient assessment. C4A null alleles are associated with chronic or recurrent rhinosinusitis, potentially through their effect on immune defence and inflammation control. Multiple clinical and immunological parameters may need to be evaluated when searching for prognostic variables.

Complement C4 Deficiency and HLA Homozygosity in Patients with Frequent Intraoral Herpes Simplex Virus Type 1 Infections

Three consecutive patients with no apparent immunodeficiency who had frequent intraoral herpes simplex type 1 recurrences, a rare complication of herpes simplex virus infection, were found to have a total deficiency of either the A or B isotype of the complement component C4 and to be homozygous for the studied HLA antigens. A combination of HLA homozygosity, which may lead to impaired T cell recognition of viral peptides, and deficiency in the classical complement pathway, which can compromise virus neutralization, may predispose to severe and frequent herpes simplex virus infections.

Mannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection

Mannose-binding lectin (MBL) is a complement component and an opsonic factor recognizing and binding to herpes simplex virus 2 (HSV-2). In this study, we assessed the effect of MBL2 genotypes on the risk of recurring HSV-2 infection. The MBL2 structural variant genotype (A/O or O/O) was more common among the patients with recurrent HSV-2 infection compared with healthy controls (47% vs 26%, respectively; odds ratio [OR] = 2.6, 95% confidence interval [CI] 1.3-4.9; p = 0.005) or controls positive for HSV-2 antibodies (15%; OR 4.9, 95% CI 1.5-16; p = 0.007). Thus, we conclude that the MBL2 structural variant genotype, possibly through impaired recognition of HSV-2, seems to predispose individuals to the development of recurring HSV-2 infection.

Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa

IMPORTANCE Mutations in the CERC1 gene associated with deficiency in the ADA2 protein (DADA2) have been implicated in the pathogenesis of cutaneous polyarteritis nodosa (cPAN) and early-onset vasculopathy. DADA2 is not only limited to cPAN and vasculopathy but also includes immunodeficiency that affects several cellular compartments, including B cells; however, some patients appear to have a more indolent, skin-limited disease. OBSERVATIONS In this report, we describe 2 white siblings (female and male) with a history of cPAN with DADA2 as a result of novel compound heterozygous mutations inherited in trans in the CECR1 gene (c.37_39del [p.K13del] and c.1159C>A [p.N328K]). The onset of disease was earlier in the female sibling than the male sibling although both were diagnosed as having cPAN in early childhood. The disease is associated with a more significant immunodeficiency and other systemic symptoms in the female than the male sibling. CONCLUSIONS AND RELEVANCE These findings suggest a genetic cause of cPAN in some patients. Therefore, DADA2 should be considered in patients with cPAN, specifically in those whose conditions are diagnosed at an early age, regardless of their ethnicity, presence or absence of systemic symptoms, or a family history of the disease.

HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis.

Sarcoidosis is a multiorgan immune-mediated disease of unknown etiology with varying clinical pictures. We studied 3 genes in the major histocompatibility complex region (HLA-DRB1 and complement C4A and C4B) in patients with resolved disease after a 2-year follow-up (n = 90) and in patients whose disease was still active at that time point (n = 98) and compared them with controls (n = 150). Our primary aim was to detect genetic differences between the patient groups. We observed that the susceptibility allele for sarcoidosis was HLA-DRB1*15:01 (p = 0.011; odds ratio [OR] = 1.67) and the protective allele was HLA-DRB1*01:01 (p = 0.001; OR = 0.43). HLA-DRB1*03:01 was associated with resolving disease when compared with the persistent group (p = 0.011; OR = 2.22). The probability of having resolving disease was even greater if the patient had HLA-DRB1*03:01 and did not have extrapulmonary lesions (p = 0.001; OR = 3.39). By evaluating amino acid variants of the HLA-DRB1 gene, we determined that specific amino acids in pockets 4, 7, and 9 were associated with the prognosis of sarcoidosis. Our results support the importance of HLA-DRB1 as a predisposing gene for sarcoidosis. Particularly, HLA-DRB1*03:01 and polymorphisms of DRB1 pocket residues were associated with a favorable prognosis. Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis.

Is there a need to redefine the diagnostic criteria for common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by decreased serum levels of immunoglobulins and abnormal antibody response to protein and/or polysaccharide antigens, leading to recurrent respiratory and gastrointestinal infections, autoimmunity and malignancies. Meanwhile, several monogenic defects with CVID-like phenotype have been identified during the last decade. There is a need to reach international consensus by modifying criteria for CVID, considering various areas of uncertainty in the field.