Immunopathology & Immunotherapy

Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) accord-ing to national and supranational registries. They are still considered rare and even of less clinicalimportance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and gen-eral practitioners but is also due to the fact that only few centers worldwide provide a comprehensivelaboratory complement analysis. To enable early identification, our aim is to present warning signs forcomplement deficiencies and recommendations for diagnostic approach. The genetic deficiency of anyearly component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune dis-eases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), arehighly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE)results in episodic angioedema, which in a considerable number of patients with identical symptomsalso occurs in factor XII mutations. New clinical entities are now reported indicating disease associa-tion with partial complement defects or even certain polymorphisms (factor H, MBL, MASPs). Mutationsaffecting the regulators factor H, factor I, or CD46 and of C3 and factor B leading to severe dysregulationof the alternative pathway have been associated with renal disorders, such as atypical hemolytic uremicsyndrome (aHUS) and – less frequent – with membranoproliferative glomerulonephritis (MPGN). Wesuggest a multi-stage diagnostic protocol starting based on the recognition of so called warning signswhich should aid pediatricians and adult physicians in a timely identification followed by a step-wisecomplement analysis to characterize the defect at functional, protein and molecular level.© 2014 Published by Elsevier