C4A deficiency in children and adolescents with recurrent respiratory infections

Kainulainen, Leena; Peltola, Ville; Seppänen, Mikko; Viander, M.; He, Qiushui; Lokki, Marja-Liisa; Ruuskanen, Olli

doi:10.1016/j.humimm.2012.02.015

Cited by 20 publications

(17 citation statements)

References 26 publications

(29 reference statements)

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“…In the recent report, C4A deficiency was suggested to predispose children and adolescents to recurrent respiratory infections. Also in this report girls predominated in patients with C4A deficiency [38] corroborating our results in NTM. Other studies have reported associations between C4B deficiency and another mycobacterial disease, leprosy [39].…”

Section: Discussionsupporting

confidence: 91%

Complement C4 Deficiency – A Plausible Risk Factor for Non-Tuberculous Mycobacteria (NTM) Infection in Apparently Immunocompetent Patients

et al. 2014

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BackgroundNon-tuberculous mycobacteria (NTM) are ubiquitous in the environment and they infect mainly persons with underlying pulmonary diseases but also previously healthy elderly women. Defects in host resistance that lead to pulmonary infections by NTM are relatively unknown. A few genetic defects have been associated with both pulmonary and disseminated mycobacterial infections. Rare disseminated NTM infections have been associated with genetic defects in T-cell mediated immunity and in cytokine signaling in families. We investigated whether there was an association between NTM infections and deficiencies of complement components C4A or C4B that are encoded by major histocompatibility complex (MHC).Methods50 adult patients with a positive NTM culture with symptoms and findings of a NTM disease were recruited. Patients' clinical history was collected and symptoms and clinical findings were categorized according to 2007 diagnostic criteria of The American Thoracic Society (ATS). To investigate the deficiencies of complement, C4A and C4B gene copy numbers and phenotype frequencies of the C4 allotypes were analyzed. Unselected, healthy, 149 Finnish adults were used as controls.ResultsNTM patients had more often C4 deficiencies (C4A or C4B) than controls (36/50 [72%] vs 83/149 [56%], OR = 2.05, 95%CI = 1.019–4.105, p = 0.042). C4 deficiencies for female NTM patients were more common than for controls (29/36 [81%] vs 55/100 [55%], OR = 3.39, 95% CI = 1.358–8.460, p = 0.007). C4 deficiences seemed not to be related to any specific underlying disease or C4 phenotype.Conclusions C4 deficiency may be a risk factor for NTM infection in especially elderly female patients.

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Section: Discussionsupporting

confidence: 91%

Complement C4 Deficiency – A Plausible Risk Factor for Non-Tuberculous Mycobacteria (NTM) Infection in Apparently Immunocompetent Patients

et al. 2014

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“…Accordingly, phenotypic C4A deficiencies have been traditionally associated with susceptibility to autoimmune diseases, whereas C4B deficiencies have shown predisposition to infections with encapsulated bacteria, acute myocardial infarction and stroke [1]–[3]. Recent studies suggests that C4A deficiency may also be linked with increased susceptibility to infections [27], [33]. The most common C4A-B combination (2 C4A and C4B genes) was significantly lower in patients than in reference population, further supporting the role of abnormal C4 CNV in aberrant immune function.…”

Section: Discussionmentioning

confidence: 99%

Copy Number Analysis of Complement C4A, C4B and C4A Silencing Mutation by Real-Time Quantitative Polymerase Chain Reaction

Paakkanen

Vauhkonen

Eronen³

et al. 2012

PLoS ONE

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Low protein levels and copy number variation (CNV) of the fourth component of human complement (C4A and C4B) have been associated with various diseases. High-throughput methods for analysing C4 CNV are available, but they commonly do not detect the most common C4A mutation, a silencing CT insertion (CTins) leading to low protein levels. We developed a SYBR® Green labelled real-time quantitative polymerase chain reaction (qPCR) with a novel concentration range approach to address C4 CNV and deficiencies due to CTins. This method was validated in three sample sets and applied to over 1600 patient samples. CTins caused C4A deficiency in more than 70% (76/105) of the carriers. Twenty per cent (76/381) of patients with a C4A deficiency would have been erroneously recorded as having none, if the CTins had not been assessed. C4A deficiency was more common in patients than a healthy reference population, (OR = 1.60, 95%CI = 1.02–2.52, p = 0.039). The number of functional C4 genes can be straightforwardly analyzed by real-time qPCR, also with SYBR® Green labelling. Determination of CTins increases the frequency of C4A deficiency and thus helps to elucidate the genotypic versus phenotypic disease associations.

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“…47 In addition, C4 plays a defensive role against virus and encapsulated bacteria. 48,49 C4 deficiency may increase the infection chances such as acute otitis media, sinusitis, or pneumonia [49][50][51] which are the exacerbating factors for IgAN resulting in a poor prognosis. [52][53][54] Someone may presume that the low C4 levels here could be caused by the activation of complement cascade.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics of IgA nephropathy associated with low complement 4 levels

Zhu

Lin

et al. 2014

Renal Failure

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Objective: C4 deficiency is the most commonly inherited immune disorder in human. The present study investigated the characteristics of the IgAN patients with low serum C4 levels.Methods: We performed a prospective observational study. Clinical as well as histopathologic parameters were assessed. A Kaplan-Meier survival analysis was performed concerning the primary outcome defined as the serum creatinine increased 1.5-fold from baseline. The prognostic significances of clinical and histopathologic parameters were determined using Cox proportional hazards models. Results: Five-hundred twelve biopsy proven IgAN cases were available for analysis with a median follow-up of 38.4 months. Ninety-nine cases (19.34%) presented with low C4 levels (LowC4 group) and the other 413 cases did not (NlowC4 group). At the time of renal biopsy, renal injury was lighter in the LowC4 group compared with the NlowC4 group. Renal C4 deposition was significantly decreased while IgM deposition was increased in the LowC4 group. A correlation analysis shows that lower C4 levels were associated with better renal presentations at biopsy. However, the risk of developing the primary outcome was significantly greater in those with low C4 levels. Specifically, during the follow-up period, the risk of developing primary outcome was nearly ten folds higher in those with low C4, compared to those without low C4. Conclusion: There is a high prevalence of low C4 levels in IgAN patients. These patients with low C4 levels exhibited better renal presentations at the time of renal biopsy, whereas might be associated with a poor prognosis.

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C4A deficiency in children and adolescents with recurrent respiratory infections

Cited by 20 publications

References 26 publications

Complement C4 Deficiency – A Plausible Risk Factor for Non-Tuberculous Mycobacteria (NTM) Infection in Apparently Immunocompetent Patients

Complement C4 Deficiency – A Plausible Risk Factor for Non-Tuberculous Mycobacteria (NTM) Infection in Apparently Immunocompetent Patients

Copy Number Analysis of Complement C4A, C4B and C4A Silencing Mutation by Real-Time Quantitative Polymerase Chain Reaction

Clinical characteristics of IgA nephropathy associated with low complement 4 levels

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