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Discussion Starter · #1 ·
The damage in type III hypersensitivity reactions are due to immune complex deposition in tissues, fixing of compliment, and the subsequent inflammatory response by neutrophils (as per Goljan and First Aid).

Berger's disease and HS-Purpura are both caused by IgA immune complex deposition. However, one of the important features of IgA is that it's constant region doesn't fix complement (otherwise we would have a persistent inflammatory reaction in our gut due to compliment fixation in response to IgA-opsonised bacteria).

So in that case, what is the pathogenesis for the inflammatory infiltrate found in patients with IgA immune complex diseases?
 

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Discussion Starter · #3 ·
IgA does not fix the Classical Pathway of complement. The theory is that the IgA immune complex of IgA glomerulonephropathy activates the alternative complement pathway.
Do you know of a reference describing this? I always was of the understanding that the alternative pathway of complement fixation was a spontaneous and ubiquitous process
 

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Do you know of a reference describing this? I always was of the understanding that the alternative pathway of complement fixation was a spontaneous and ubiquitous process
Rubin's Pathology text.

'IgA-containing immune complexes within the mesangium most likely activate the alternative complement pathway. This concept is supported by the demonstration of C3 and properdin, but not C1q and C4, in the IgA deposits.'
 

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Scientific Basis for Complement
Activation in IgAN
In addition to mesangial IgA deposits, biopsies of IgAN are commonly
associated with the deposition of complement components, most notably
C3, the membrane attack complex (C5b-9), and properdin,1–3 suggesting
the participation of complement activation in disease pathogenesis.
Early reports demonstrated the expression of C3, C4 and factor B
in proximal tubular epithelial cells, mesangial cells, glomerular epithelial
cells, Bowman’s capsule, and infiltrating mononuclear cells in the
interstitium in patients with IgAN.4,5
These data suggest that local complement production6,7 by various
intrinsic renal cells and infiltrating cells may contribute to tissue injury
in IgAN. In support of this notion, local C3 transcription and translation
has been found to correlate with clinical and histologic markers of
severity and poor outcome of IgAN.8 Moreover, proteinuria but not
serum creatinine, at the time of renal biopsy correlated with C3 mRNA
expression. This last phenomenon may be attributed to the finding that
apical proteins stimulated basolateral C3 synthesis by cultured human
proximal tubular epithelial cells,9 in which transferrin and apotransferrin
stimulated C3 biosynthesis more intensely.10 Locally secreted C3 may
further activate tubular cells via the C3a receptor11 to enhance renal
injury. This is supported by the observation of increased levels of split
products of activated C3 in the circulation of patients with IgAN that are
associated with increased proteinuria and hematuria, highlighting the
activate the alternative
pathway of complement directly, whereas monomeric IgA is a poor
activator of the complement system.13 The molecular basis for the
difference between monomeric IgA and pIgA is not clear.
More recently, two Japanese groups14,15 reported that the serum
IgA/C3 ratio may reflect the histological severity of IgAN and could
serve as a marker of the progression of IgAN, and may be useful for
prediction of diagnosis of IgAN and distinguishing it from other renal
diseases. Another German study16 indicated that only alternative pathway
complement activation can be demonstrated in patients with IgAN
and its activation was associated with more severe renal disease. The
clinical significance of such correlation studies requires confirmation.
Potential Role of the Lectin Pathway
The recently described lectin pathway of the complement system
forms an integral component of innate immunity. The key molecule
of this pathway, mannose-binding lectin (MBL), binds directly to a
number of microorganisms via carbohydrates expressed on their surface17
to activate complement as a first line host defense mechanism against
pathogens. It is therefore not surprising that MBL may interact with
IgA, an important mediator of mucosal immunity, and assume a role
in IgAN.
Evidence is accumulating that complement activation via MBL and
the lectin pathway is associated with disease progression in IgAN.18,19
It has been shown that MBL is able to bind pIgA, leading to activation
of the lectin pathway in vitro.20 However, there is no difference
in the binding of MBL to IgA from healthy subjects or patients with
IgAN.21 The carbohydrate recognition domain of MBL is able to bind
in a calcium-dependent manner to a number of saccharides, such as
D-mannose, L-fucose, and N-acetylglucosamine, whereas the binding
of MBL to IgA has been proposed to be mediated through the oligomannose
structures present in the N-linked sugars of the heavy
chains of pIgA.21
Deposition of MBL in association with IgA as a marker for lectin
pathway activation has been reported,18,19,22 but these findings were not
consistently reproduced.23 Furthermore, the relationship of glomerular
MBL deposition with parameters of renal damage and complement
activation via the lectin pathway is inconsistent among different studies.
More recent data suggest that IgA was co-deposited with MBL in
about 25% of patients and that MBL deposition showed more severe
renal disease as compared with MBL-negative cases, suggesting an
important role for MBL in disease progression.24 These results rekindled
the notion that activation of the lectin pathway occurs in a subpopulation
of patients, and that MBL deposition may serve as a biomarker for
disease progression in IgAN.
Conclusion
There is evidence to suggest that activation of the alternative and lectin
pathways of the complement cascade occurs in IgAN, and that such activation
may provide prognostic value. For both pathways, pIgA is a more
potent activator than monomeric IgA. Research interest in this area has
been most intense in the last two decades, but appears to have dampened
in recent years. The putative pathogenetic role of complement
activation and its predictive and prognostic values remain to be elucidated
more carefully. Findings at the biopsy level emphasize the importance
of further delineating the precise composition of IgA in mesangial
deposits because ultimately these data may unravel the mechanisms
involved in IgA deposition and complement activation in IgAN.
 
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