Diseases of complement dysregulation-an overview

Abstract

Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.

Keywords: C3G, aHUS; Complement; PNH.

Fig. 1

The role of complement in thrombotic microangiopathies. A mutation or autoantibody resulting in complement dysregulation predisposes to complement-mediated aHUS. Complement-mediated aHUS frequently only manifests upon exposure to an environmental trigger, which can include other causes of TMA. In some TMAs, a high proportion of individuals carry a mutation (e.g., pregnancy associated aHUS, ~ 70%, and de novo post-transplant TMA, ~ 30%) but in others the incidence of mutations is unknown or low (e.g., STEC-HUS). In other TMAs, complement activation may be seen in vivo but whether it plays a role as a disease modifier or is simply a bystander is yet to be clarified

Fig. 2

Overlap of C3G and MPGN. A cause of uncontrolled complement activation should be suspected in cases of C3 glomerulopathy (bold circle). Specific forms of C3G include C3GN, DDD, and CFHR5 nephropathy. Light microscopy identifies a diverse pattern of glomerular injury that includes MPGN. Uncontrolled complement activation has also been identified in cases of immune-complex MPGN (shaded)—these are cases of MPGN that do not fulfill current criteria for C3G. Causes of uncontrolled complement activation should be considered in an overlapping group of C3G and MPGN

Fig. 3

FHR1, FHR2, and FHR5 have a dimerization motif but lack regulatory domains. Shaded ovals denote regulatory and recognition domains of FH. Percentages shown within ovals of FHR proteins indicate degree of shared homology with corresponding SCR of FH depicted directly above. FHR proteins do not have shared homology with the regulatory domains of FH. However, SCR1 and 2 of FHR1, FHR2, and FHR5 (patterned ovals) have a high degree of shared homology with each other—highlighted in boxed inset. These domains share a dimerization motif