Hereditary C2 Deficiency in Sweden

Abstract

Although frequently asymptomatic, homozygous C2 deficiency (C2D) is known to be associated with severe infections and rheumatic disease. We describe the clinical findings in 40 persons with C2D from 33 families identified in Sweden over 25 years. Medical records covering 96% of the accumulated person-years were reviewed, giving a mean observation time of 39 years (range, 1-77 yr). Severe infection was the predominant clinical manifestation in the cohort: 23 patients had a past history of invasive infections, mainly septicemia or meningitis caused by Streptococcus pneumoniae, and 12 patients had repeated infections of this kind. Nineteen patients had at least 1 episode of pneumonia, and recurrent pneumonia was documented in 10 patients. Repeated infections occurred mainly during infancy and childhood. Systemic lupus erythematosus was found in 10 patients. Another 7 patients had undifferentiated connective tissue disease (n = 4) or vasculitis (n = 3). We found no correlation between susceptibility to invasive infection and rheumatologic disease. Cardiovascular disease occurred at a high rate, with a total of 10 acute myocardial infarctions and 5 cerebrovascular episodes in 6 patients. Causes of death among the C2D patients were infection (n = 5), acute myocardial infarction (n = 3), and cancer (n = 1). We suggest that severe infection may be the principal clinical manifestation of C2D. We also provide novel evidence for a possible role of C2D in the development of atherosclerosis consistent with findings in mannan-binding deficiency and experimental C3 deficiency. In addition, we confirm the well-known association between C2D and systemic lupus erythematosus.

Complement Defects in Patients with Chronic Rhinosinusitis

“…In the study by Seppänen and colleagues they found a strong association between C4A null alleles and CRS. Another work showed relative high but non-statistically tested occurrence of severe and minor infections – including recurrent sinusitis – in patients with C2 deficiencies [19]. Our findings and partly also Seppänen and colleagues findings, are in contrast with previous work showing lack of association between C3, C4 and MBL deficiencies and CRS [23].…”

“…Unlike the current study, others have addressed associations between complement defects and CRS by studying single components, and by means of estimations of serum concentrations and genotyping [19], [23], [24]. One can argue that the great redundancy of the complement system where: isoforms overlap in function, number of gene copies varies and pathways merge, and also partly overlap in function makes it difficult to interpret the importance of a given association.…”

Association between Toll-like receptor 9 gene polymorphisms and risk of bacterial meningitis in a Chinese population

“…Recent epidemiologic studies have shown that genetic polymorphisms in the activation pathway proteins C2 (classical pathway), factor D (alternative pathway), and properdin (alternative pathway) are associated with the development of pneumococcal and meningococcal diseases (Jönsson et al, 2005;Sprong et al, 2006;Ricklin et al, 2010). Toll-like receptors (TLRs) constitute a major family of pathogen recognition receptors that are expressed in various cells inside the central nervous system, such as microglia and astrocytes, and recognize pathogenassociated molecular patterns.…”

Effects of Streptococcus pneumoniae Strain Background on Complement Resistance

“…The vital role of complement for immunity to S. pneumoniae [1], [2], [3], [4], [10], [39] suggests that differences in complement sensitivity could affect the relative invasiveness of S. pneumoniae strains, and so evaluating factors influencing S. pneumoniae complement resistance is an important area of research. Data obtained using capsular serotype switched strains has confirmed capsular serotype is one factor that affects the sensitivity of different S. pneumoniae strains to complement [24], [25], [26].…”

“…Immunity to S. pneumoniae is highly dependent on the complement system [1], [2], [3], [4], a series of host serum and cell surface proteins organised into three enzyme cascades termed the classical, alternative and mannan binding lectin (MBL) pathways. The classical pathway is activated by specific antibody [5], and by recognition of S. pneumoniae cell wall phosphorylcholine (PC) by natural IgM or the serum pentraxin proteins C reactive protein (CRP) and serum amyloid P (SAP), or by binding of the capsule to the lectin SIGN-R1 [2], [6], [7], [8].…”