What is the pathophysiology of Henoch-Schönlein purpura (IgA vasculitis)?

Updated: Oct 28, 2020
  • Author: Rajendra Bhimma, MBChB, MD, PhD, DCH (SA), FCP(Paeds)(SA), MMed(Natal); Chief Editor: Craig B Langman, MD  more...
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IgA clearly plays a critical role in the immunopathogenesis of IgAV, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls of affected organs and in the kidney mesangium. Deposition of IgA aggregates or IgA complexes in target organs occurs with activation of the alternative complement pathway (with deposition of C3). This results in an elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, that may play a central role in the pathogenesis of IgAV and its organ-specific clinical manifestations.ref130}

IgA is found in the serum and mucosal secretions and is a major class of immunoglobulins that plays an important role in mucosal immunity. IgAV is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. IgA1 is phylogenetically younger and differs from IgA2 by insertion of a 13-17 amino acid sequence in the hinge region of the IgA1 molecule. [22] The predominance of IgA1 in IgAV may be a consequence of abnormal glycosylation of O-linked oligosaccharides unique to the IgA1 hinge region. Patients with IgAV and IgA nephritis express inherited galactose-deficient glycosylation of IgA1 molecules. [23]

IgAV-associated nephritis is characterized by an abnormal IgA1 glycosylation pattern with reduced galactosylation. [24] The hinge region of IgAcontains up to six major glycosylation sites at serine and threonine residues. The O-glycans include a core N-acetylgalactosamine (GalNAc), which is usually extended with galactose to form Galβ1,3GalNAc, which can bind to N-acetylneuraminic acid (Neu5Ac). Thus, each IgAO-glycan can have one of four short carbohydrate structures (types III, IV, V, and VI), leading to a mixture of IgA1 forms with varying degrees of galactosylation.

Patients with IgAV-associated nephritis have a high prevalence of galactose-deficient (types I and II) IgA1. [24]  The lack of terminal β1,3-galactosyl residues in the hinge region of IgA might be due to reduced activity of β1,3-galactosyltransferase in IgA1-producing peripheral B cells. This reduction of galactosylation results in exposure of GalNAc residues in the IgAsurface, forming a novel antigen and inducing a humoral IgG autoimmune response. [25]  

Circulating complexes of mixed IgG and galactose-deficient IgAare not only detected in patients with IgAV but also in the serum of patients with mucosal infections. [26]  The finding that galactose-deficient IgA1 molecules are only found in IgAV during an episodes of nephritis lends support to the pathophysiological role of galactose-deficient IgA1 molecules in IgAV nephritis. [27]

A subpopulation of human lymphocytes bears surface Fc and/or C3 receptors (complement receptor lymphocytes), which can bind circulating immune complexes or C3 generated by activation of the alternative complement pathway. Such immune complexes appear in IgAV and may be part of the pathogenetic mechanism.

Some have speculated that an antigen stimulates the production of IgA, which, in turn, causes the vasculitis. Allergens, such as foods, horse serum, insect bites, exposure to cold, and drugs (eg, ampicillin, erythromycin, penicillin, quinidine, and quinine), may precipitate the illness. Infectious causes include bacteria (eg, Haemophilus parainfluenzae, Mycoplasma, Legionella, Yersinia, Shigella, or Salmonella) and viruses (eg, adenoviruses, Epstein-Barr virus [EBV], parvoviruses, or varicella-zoster virus [VZV]). Vaccines such as those against cholera, measles, paratyphoid A and B, typhoid, and yellow fever have also been implicated. However, there is no evidence supporting a direct role of herpesvirus, retrovirus, or parvovirus infection in the pathogenesis of IgAV.

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