We report an association between a non-familial form of photosensitive Lupus-specific skin disease, subacute cutaneous lupus erythematosus (SCLE), and a new single nucleotide polymorphism (SNP) in the C1QA gene. We also describe an association between this SNP and lower levels of serum C1q. This SNP consists of adenine replacing the third guanine in the codon for aminoacid residue Gly70 (position excludes the 22 amino acid leading peptide) that is located in the second exon of the C1QA gene. We have designated this SNP C1qA-Gly70GGA (the GenBank sequence at this location is C1qA-Gly70GGG). A survey of 19 SCLE patients showed that 11 (58%) were homozygous for C1qA-Gly70GGA SNP, seven (37%) were heterozygous, and only one patient (5%) was homozygous for the GenBank sequence. In contrast, only 13 of 62 (21%) normal controls were homozygous for the C1qA-Gly70GGA SNP, 41 (66%) controls were heterozygous and eight (13%) controls were homozygous for the GenBank sequence. Thus, the C1qA-Gly70GGA SNP is strongly associated with SCLE (P-value = 0.005 by chi-square analysis with Yates correction). This SNP would traditionally be classified as clinically silent as it does not encode a different amino acid. However, our studies have suggested that this SNP appears to be associated with a functional abnormality of C1q expression since its presence correlates inversely with serum levels of C1q antigenic protein in both SCLE patients and normal controls. The mechanism by which this phenotypic change is associated with the translationally silent (synonymous) ClqA-Gly70GGA genetic variation is currently unknown.

The complement cascade is a multi-faced effector component of the innate immune response. C1q is the recognition component of the classical pathway of complement activation. In addition, C1q has been recognized to serve a number of other biological functions including a modulating role on cellular functions within the adaptive immune response. The importance of C1q to normal immune regulation is reflected by the fact that greater than 90% of individuals who have complete congenital deficiency of C1q have been observed to develop early-onset photosensitive systemic lupus erythematosus (SLE). As a number of single nucleotide polymorphisms have been identified in three C1q genes, it is possible that more subtle variations in C1q expression could be a risk factor for cutaneous LE and SLE. Thus, a more comprehensive delineation of complotype could be of increasing clinical importance in the future.

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Multiple factors, including expression of costimulatory molecules, antigen-presenting molecules, and target antigens, likely impact the efficacy of antibody therapy and other approaches to the immunotherapy of B cell malignancy. Unmethylated CpG-dinucleotides in select base contexts (“CpG motifs”) that resemble sequences found in bacterial DNA are potent immunostimulatory agents capable of inducing a complex immune response, including a strong B cell stimulus. We examined the effect of a potent human CpG oligonucleotide (CpG ODN 2006) on different types of primary human malignant B cells and reactive follicular hyperplasia. CpG oligodeoxynucleotide (CpG ODN), but not control (non-CpG ODN), increased the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on malignant B cells without altering the phenotype of B cells obtained from reactive follicular hyperplasia. CpG ODN also enhanced expression of class I and class II MHC in most samples. CD20 expression was increased in response to CpG ODN, most notably in B-CLL and marginal zone lymphoma. An inverse correlation was found between baseline expression of CD20 and CD40 and their expression after exposure to CpG ODN, thus the most significant increase in expression of these molecules was found in those samples that had the lowest baseline levels. In conclusion, CpG ODN can lead to increasing expression of molecules involved in costimulation, antigen presentation, and as targets for antibody-based therapy and deserve further evaluation as potential immunotherapeutic agents for B cell malignancy.