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Response to: ‘Serum complement factor C5a in IgG4-related disease’ by Fukui et al
  1. Hisanori Umehara1,
  2. Mitsuhiro Kawano2
  1. 1 Division of RA and Autoimmune Diseases, Nagahama City Hospital, Shiga, Japan
  2. 2 Division of Rheumatology, Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
  1. Correspondence to Professor Hisanori Umehara, Division of RA and Autoimmune Diseases, Nagahama City Hospital, Shiga 526-8580, Japan; umehara606{at}

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We appreciate the interest shown by Dr S Fukui and colleagues1 in our recent paper, ‘How to diagnose IgG4-related disease (IgG4-RD)’.2

IgG4-RD is characterised by increased serum IgG4 concentrations and number of IgG4-positive plasma cells in affected lesions.3 However, its diagnosis can be difficult, because clinical signs vary depending on the organs affected.

A Japanese team established comprehensive diagnostic criteria for IgG4-RD, 2011 focusing on the concentration of serum IgG4 (>135 mg/dL), numbers of IgG4-positive cells (>10 cells/HPF) and ratio of IgG4-positive to IgG-positive cells (>40%) in affected tissues.4

However, many cases of IgG4-RD with low levels of IgG4 and mimickers of IgG4-RD with increased serum IgG4 have been reported and the concept of IgG4-RD has become blurred. Therefore, new specific markers or new criteria for IgG4-RD are required.5

Human IgG4 has a unique structure distinguished from the other IgG subclasses by lack of interaction with the complement system and inability to activate the classical complement pathway.6 7 However, hypocomplementaemia has been observed in IgG4-RD ever since the concept was first established8 and is in particular more frequent and sometimes severe in IgG4-related kidney disease.9 A recent study showed that non-IgG4 IgG such as IgG1, which can activate complement, might be involved in the activation of complement in IgG4-RD.10

Fukui et al reported the significant increase of C5a in IgG4-RD and suggested it for a therapeutic target.1 However, serum C5a elevation is also a very important feature of active systemic lupus erythematosus (SLE). Since elevated C5a levels in IgG4-RD are much lower than in active lupus cases11 and only some groups of patients with IgG4-RD have hypocomplementaemia, the production of C5a in SLE and IgG4-RD likely exhibits significant differences in both underlying mechanism and pathogenetic role.

Although the details of the pathogenesis of IgG4-RD are unclear at present, recent basic studies have implicated the toll-like receptor (TLR) signalling pathway.12 Activation of C5aR in macrophages inhibits TLR-4 signals resulting in reduction of IL-12, IL-23 and IL-27 production by inflammatory macrophages.13 Thus, the role of cross-talk between innate and acquired immunity through the complement pathway and TLR system is attracting attention in the pathogenesis of IgG4-RD.14



  • Handling editor Josef S Smolen

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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