Background/Purpose: Juvenile Dermatomyositis (JDM), a systemic vasculopathy, is member of the family of autoimmune diseases. In 56% of untreated JDM, a decrease in the absolute number of natural killer cells reflects immune activation and increased disease activity. JDM is also associated with B*08, DRB1*03, DQA1*0501, C4B1, C4AQ0 (null), and TNFA-308A polymorphism, in linkage disequilibrium on chromosome 6.  In the families of children with JDM, there is a significant increase in the history of systemic lupus erythematosus (SLE). Patients with SLE, have an overrepresentation of C4A null alleles, with associated decreased levels of the C4 protein. The frequency of C4A deficiency in children with JDM is unknown. Objective:To determine the association of C4 protein and other clinical parameters with C4A gene copy number in JDM.

Methods: A cross-sectional cohort of children, n=91, with definite/probable JDM (overlap syndromes excluded) were enrolled (IRB# 2008-13457).  There were 78% (71/91) girls, 96.7% (88/91) White, mean age of 5.06 yrs, and 35% (32/91) were untreated at time of first visit.  Genomic DNA was assessed for gene copy number (GCN) for total C4, C4A and C4Bby real time qPCR; EDTA-plasma was used to determine C4A and C4B polymorphisms and validate genotype data.  Data for C4 protein concentrations, disease activity scores (DAS) for skin involvement and muscle weakness were obtained, along with nailfold capillary end row loop number, and absolute cell count of CD3negative, CD56/16 positive natural killer (NK) cells at time of first visit.  NHANES normative data obtained from 523 subjects for C4A gene copy number were used as a comparator.

Results: Patients with JDM have lower C4A GCN than the general population (30% vs. 17% with 0-1 copy, p=0.009, Chi-square test). The level of C4 protein was significantly associated with the C4 total gene copy number, p<0.001; the C4 protein levels increases by 3.61 unit/one C4 copy number. The C4 protein concentration was not significantly associated with any of the following: nailfold capillary end row loop number, DAS skin or DAS muscle.  However, there was a significant association of the C4AGCN with the absolute number of circulating CD3negative NK cells in JDM (p=0.02).

Conclusion: Children with JDM have decreased levels of C4 protein as a function of significantly decreased GCN of C4. Although the decreased C4 was not associated with nailfold capillary end row loop numbers, or clinical disease activity markers, the C4A GCN appeared to be associated with the absolute levels of circulating NK cells, suggesting a locus of control on chromosome 6.  We speculate that the decrease in C4 as a consequence of C4A GCN may contribute to the pathogenetic mechanisms of damage in JDM.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/decreased-c4a-gene-copy-numbers-in-children-with-juvenile-dermatomyositis-association-with-decreased-c4-protein-and-lower-absolute-number-of-cd3-negative-cd1656-natural-killer-cells/