Henoch-Schönlein purpura pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

• HSP is a small vessel leukocytoclastic vasculitis, but its pathophysiology is not completely understood.
• Researchers have found elevations in the serum levels of immunoglobulin (Ig) A, IgA-containing circulating immune complexes and IgA rheumatoid factors in patients with HSP.
• Therefore, it generally believed that HSP is an immune complex-mediated disease, because HSP is frequently reported to follow respiratory tract infections, a variety of viral and bacterial pathogens have been implicated as triggers of the disease.
• It has been reported that all patients with HSP have small molecular mass IgA1-containing circulating immune complexes, but only those with HSPN have additional large molecular mass IgA1-IgG-containing circulating immune complexes.
• The IgA1 molecule has a hinge region containing up to six O-linked glycan chains[16,17] consisting of N-acetylgalactosamine, usually

with an attached β1,3-linked galactose.

• It has been reported that in patients with HSPN, the activity of β1,3-galactosyltransferase in peripheral B cells is reduced, leading to a lack of terminal β1,3-galactosyl residues in the hinge region of IgA1.
• The primary defect leading to the production of such abnormally glycosylated IgA1 is probably heritable.
• These aberrantly glycosylated IgA1 molecules have been shown to form immune complexes with IgG antibodies specific for galactose-deficient IgA1, thereby inhibiting the binding of the IgA molecules to hepatic receptors and avoiding their internalization and degradation by hepatic cells.
• This formation results in an increased amount of IgA immune complexes in circulation.
• The complexes may then deposit in renal mesangial areas and activate the complement system by the alternative or lectin pathways, which play a major role in the pathophysiology of this disease.
• Further, after depositing in the mesangium, the galactose-deficient IgA1 immune complexes activate mesangial cells.
• This results in the proliferation of cells such as macrophages and lymphocytes and the production of inflammatory and profibrogenic cytokines and

chemokines, which play a pivotal role in mesangial cell proliferation, matrix expansion, and inflammatory cell recruitment.

• There are also other possible pathogenetic mechanisms of HSPN, because throat cultures positive for group A beta-hemolytic streptococcus have been

found in 20%-30% of patients with HSPN, it is thought that nephritis-associated plasmin receptor, a group A streptococcal antigen, may also be responsible for some of the cases of HSPN.

• In addition, eosinophil activation and renal expression of alpha-smooth muscle actin have been reported to play a role in the

pathogenesis of HSPN.