Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22).

BACKGROUND: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. OBJECTIVE: We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. METHODS: We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. RESULTS: C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells. CONCLUSION: The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.

Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency?

Analysis of cancer risk in primary immune deficiency (PID) offers insight into the relationship between immune function and cancer. Data on Australian patients (n = 1132) notified voluntarily to the Australasian Society of Clinical Immunology and Allergy PID Registry (1990-2008) were linked with national death and cancer registries. Person-years of follow-up commenced from up to 15 years before registration on the PID Registry or January 1982, the inception of national cancer registration. Site-specific, 5-year age-, sex-, calendar year-, and state-standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs) were calculated for all cancers except nonmelanocytic skin cancer. During an average of 16 person-years follow-up, a 1.6-fold excess relative risk of cancer was observed (n = 58; SIR 1.60, 95% CI 1.22-2.07) for all PID combined. Relative risk was increased for non-Hodgkin lymphoma (n = 16; SIR 8.82, 95% CI 5.04-14.30), leukemia (n = 4; SIR 5.36, 95% CI 1.46-13.73), and stomach cancer (n = 3; SIR 6.10, 95% CI 1.26-17.84). Excess cancer risk was observed for predominantly antibody deficiencies and other well-defined immunodeficiency syndromes. Results suggest that predominantly antibody deficiencies may be associated with a narrower range of solid cancers than immunodeficiency characterized by predominantly T-cell deficiency, such as iatrogenic and HIV-related immunodeficiency, although this requires confirmation in larger cohorts.

Primary immunodeficiency diseases in Australia and New Zealand.

INTRODUCTION: Despite rapid developments in the science of primary immunodeficiency diseases (PID), population characteristics and the burden of disease are poorly characterized. Aggregated data on PID via patient registries are a key component of the public health response. The web-enabled Australasian Society of Clinical Immunology and Allergy PID Register was designed and implemented to address gaps in knowledge of PID. METHODS: The register provided a cumulative, cross-sectional survey of PID patients in Australia and New Zealand via an online, single time point, center-based, voluntarily recalled, and patient-consented questionnaire. RESULT: Eighty-eight centers reported 1,209 patients across 56 separate PID syndromes. The study prevalence (cases per 100,000 population) was 5.6 for Australia, 12.4 for the state of South Australia, and 4.9 for Australia and New Zealand combined. Predominately antibody deficiency syndromes accounted for 77% of patients. Common variable immunodeficiency was the most common diagnosis. Patients were geographically dispersed with 80% of centers reporting caseloads of less than 20 patients. Potentially preventable complications of disease were common. Immunoglobulin replacement therapy was used in 30 conditions with 26.5% of the total recipients having antibody deficiency disorders with normal serum IgG. CONCLUSION: PID in Australia and New Zealand are prevalent, clinically diverse, geographically dispersed, and are characterized by high rates of potentially preventable morbidity and resource utilization. A public health focus on PID is required, including strategies to correct disparities in access to care, improve molecular diagnostics and reduce preventable complications of disease. Further studies in antibody deficiency syndromes with normal serum IgG are required.

Antibodies to cyclic citrullinated peptide in patients with chronic arthritis attending an arthritis-monitoring clinic.

BACKGROUND: Early diagnosis of rheumatoid arthritis allows prompt initiation of antirheumatic therapy, which is associated with improved outcome. The use of IgM rheumatoid factor, the most widely used serologic test in assisting the diagnosis of rheumatoid arthritis, is limited by low specificity. An enzyme-linked immunosorbent assay test detecting antibodies to cyclic citrullinated peptide (CCP) has been developed with apparently higher specificity for rheumatoid arthritis. AIM: We aimed to evaluate an assay for anti-CCP antibodies by determining the prevalence and titer of antibodies to CCP in a group of patients with chronic arthritis. METHOD: Thirty-four sera were collected from outpatients attending an arthritis-monitoring clinic and tested for anti-CCP and IgM rheumatoid factor. RESULTS: Anti-CCP and rheumatoid factor were detected in 86% and 72% of patients with rheumatoid arthritis, respectively. Six patients negative for rheumatoid factor were positive for anti-CCP. CONCLUSION: Anti-CCP antibodies are frequently detectable in high titer in patients with longstanding rheumatoid arthritis. This assay may be especially helpful in such cases when positive in rheumatoid factor-negative patients.