Galactose-deficient IgA1 in skin and serum from patients with skin-limited and systemic IgA vasculitis

Abstract

Background: IgA-vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactosedeficient IgA1 (GD-IgA1) in kidneys (as in IgA-nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown. Objective: We investigated if GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV, and if its serum levels differ between both forms. Methods: In a case control study, deposition of GD-IgA1 was analysed immunohistochemically by KM55-antibody in skin biopsies from 12 patients with skin-limited and 4 with systemic IgAV. GD-IgA1levels were compared by ELISA in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy subjects. Results: All biopsies from systemic, but also from skin-limited IgAV revealed perivascular GD-IgA1deposition. The average GD-IgA1-level in serum was significantly higher in systemic than in skinlimited IgAV, despite overlap between both groups. Limitations: Although high GD-IgA1-levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV. Conclusion: While perivascular GD-IgA1-deposition is a prerequisite for systemic and skin-limited IgAV, high GD-IgA1-levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV.

Pathogenesis of IgA Vasculitis: An Up-To-Date Review

“…Reduced galactosylation in the O-glycan site of the hinge region of IgA1 was detected in patients with IgAV, especially IgAV-N (63,86,87). Recent findings of Gd-IgA1in the cutaneous lesions and clinically uninvolved skin in skin-limited IgAV further confirmed its role in IgAV (62). The serum level of Gd-IgA1-specific IgG is associated with disease activity and renal involvement (85).…”

“…And some clinical studies suggested that the serum levels of Gd-IgA1 or Gd-IgA1-CIC in IgAV patients without nephritis are the same against healthy controls ( 63 , 86 ). However, in a recent study, Gd-IgA1 was detected using KM55 staining in the skin of IgAV patients without nephritis ( 62 ). The result suggested that Gd-IgA1 are important in both systemic and organ limited IgAV.…”

“…The formation of IgA-CIC hinders the liver clearance of these immune complexes, and overloaded IgA-CIC can deposit at vessel walls (102)(103)(104)(105). Deposition of Gd-IgA1 containing immunocomplex can be found in small vessel walls in the skin as well as the kidney and mesangial cells (62). The serum level of Gd-IgA1 is not correlated with the intensity of Gd-IgA1 deposits in the kidney and skin, suggesting that factors other than size and amount of CIC influence the deposition of immune complexes and other mechanisms are involved in the deposition of Gd-IgA1 (65).…”

“…A widely accepted hypothesis for the pathogenesis for IgAN is a multi-hit model proposed by Novak J. et al ( 61 ). The model was originally used in IgA nephropathy but later found applicable in IgAV ( 62 , 63 ). In this model, the first and second hit is the production of Gd-IgA1 and autoantibodies against Gd-IgA1, the third hit is the formation of Gd-IgA1 containing immune complexes, and finally, the fourth hit is the deposition of immune complexes in tissue activates the inflammatory process that results in organ injury ( 62 – 65 ) ( Figure 1 ).…”

A Review of the Mechanism of Vascular Endothelial Injury in Immunoglobulin A Vasculitis

“…In IgAV, galactose-deficient IgA1 (Gd-IgA1) can be detected not only in the serum but also in the skin and kidney tissue ( Neufeld et al, 2019 ; Oni and Sampath, 2019 ; Zhang et al, 2020 ), and IgA1-containing immune complexes, especially IgA1 accumulation in vessel walls, promote the development of IgAV. A multi-hit hypothesis is generally considered to illustrate the role of Gd-IgA1 in the pathogenesis of IgAV.…”