IgA Immune System

IgA is the most abundant immunoglobulin in the body and is chiefly concerned with mucosal defense. It has two subclasses, IgA1 and IgA2. Mucosal antigen challenge provokes polymeric IgA (pIgA) production by plasma cells of the mucosa-associated lymphoid tissue; the pIgA is then transported across epithelium into mucosal fluids, where it is released after coupling to secretory component as secretory IgA (sIgA). The function of circulating IgA is less clear; it is bone marrow derived and mostly monomeric IgA1 (mIgA1). Circulating IgA1 is cleared by the liver through hepatocyte asialoglycoprotein receptors and Kupffer cell Fcα receptors.

The mesangial IgA in IgAN is predominantly pIgA1. The clinical association with mucosal infection or superantigens from Staphylococcus aureus originally suggested that the mesangial pIgA1 comes from the mucosal immune system. In IgAN, however, pIgA1 production is downregulated in the mucosa and upregulated in the bone marrow. Moreover, the pIgA response to systemic immunization with common antigens is increased, whereas the response to mucosal immunization is impaired. Impaired mucosal IgA responses allowing enhanced antigen challenge to the marrow could be the primary abnormality in IgAN, although this remains unproven. Similarly attractive, yet still unproven, is the hypothesis that some mucosal IgA-producing plasma cells translocate to the bone marrow in IgAN; this could also explain the particular glycosylation of serum IgA in IgAN. Tonsillar pIgA1 production is also increased, although IgAN can occur after tonsillectomy, and the tonsil is a very minor source of IgA production compared with the mucosa or marrow. There are reports of sIgA in the mesangium, but this finding is not easily explained by current pathogenic concepts of IgAN. Hepatic clearance of IgA is reduced, possibly because of the altered molecular characteristics of IgA in IgAN (see later discussion).

Serum IgA levels are increased in one third of patients with IgAN and HSP. There are elevations in both mIgA and pIgA. However, high serum IgA itself is not sufficient to cause IgAN. High circulating levels of monoclonal IgA in myeloma or polyclonal IgA, in acquired immunodeficiency syndrome (AIDS), only infrequently provoke mesangial IgA deposition.

Circulating macromolecular IgA is characteristic of IgAN. It is often described as IgA immune complexes, although the antigen is only rarely identified. There are circulating IgA rheumatoid factors (IgA against constant domain of IgG) in 30% of patients with IgAN and 55% of those with HSP. Studies in vitro indicate that IgA production by mononuclear cells is exaggerated in IgAN, and that these cells show abnormal patterns of cytokine production. However, the direct relevance of these observations to events in vivo is uncertain.

IgA Glycosylation

IgA1 carries distinctive O-linked sugars at its hinge region; IgA2 has no hinge and carries no such sugars. There is good evidence that circulating IgA1 in IgAN and HS nephritis has abnormal O-linked hinge-region sugars with reduced galactosylation because of altered IgA production in lymphocytes of patients with IgAN.¹ Some data indicate defective function of the relevant glycosyltransferases that O-glycosylate IgA1, possibly with a genetic basis. Other findings suggest that the primary abnormality may be that IgA of mucosal type, which has glycosylation patterns different from serum IgA1, reaches the circulation, for example, by translocation of mucosal lymphocytes to the bone marrow. The latter is consistent with experiments, where immortalized lymphocytes from IgAN patients continue to produce dimeric and polymeric IgA with altered galactosylation in vitro.²

Mesangial IgA1 in IgAN has the same abnormalities of O-glycosylation.^3,4 The altered glycosylation may lead to IgG anti-IgA autoantibodies and promote mesangial IgA1 deposition by predisposing to the formation of circulating IgA1 immune complexes or by directly modifying IgA1 interactions with matrix proteins and mesangial cell or monocyte Fc receptors.⁵ It may also impair IgA1 clearance by inhibiting IgA1 interactions with hepatic and circulating myeloid cell IgA receptors. Figure 23-1 summarizes some key elements involved in the pathogenesis of IgAN.

Polymeric IgA deposition in the mesangium is typically followed by mesangial proliferative glomerulonephritis (GN). In animal models, co-deposition of IgG and complement is necessary for inflammation, but this is not mandatory in human disease. Complement deposits are usually C3 and properdin without C1q and C4. There may be complement activation via the mannose-binding lectin pathway. The extent to which IgA engages inflammatory cells in the circulation and especially in the kidney will determine the intensity of inflammation. Fc receptors for IgA (Fcα receptors) on myeloid and mesangial cells may play a key role.⁶

The mechanisms of mesangial proliferative GN have been studied in detail in animal models, particularly anti–Thy 1 nephritis in the rat. These studies have shown the key role of cytokines and growth factors in mesangial cell proliferation, particularly the B and D isoforms of platelet-derived growth factor⁷ (PDGF) and in the subsequent matrix production and sclerosis, particularly transforming growth factor-β (TGF-β). Studies of renal biopsy specimens in human IgAN also support a role for PDGF and TGF-β. These mechanisms are not unique to IgAN but are likely involved in all forms of mesangial proliferative GN, including those without IgA deposition.

Animal Models of IgA Nephropathy

Animal IgA does not have the same characteristics as human IgA1, and some animals also have IgA clearance mechanisms distinct from those in humans. Therefore, animal models, even if they provoke mesangial IgA deposits, are not particularly informative about the mechanisms that underlie human mesangial pIgA1 deposition, although they have provided many insights into events after IgA deposits have developed. There is no animal model in existence for HSP.

Relationship Between IgA Nephropathy and Henoch-Schönlein Purpura

Despite some differences in age at onset and natural history of IgAN and HS nephritis,⁸ there is much evidence to support a close pathogenetic link between the two conditions, and the outcome of the two diseases may be similar.⁹ Monozygotic twins who developed IgAN and HSP, respectively, at the same time have been described. The evolution of IgAN into HSP in the same patient is described in both adults and children, and HSP patients with ESRD receiving a renal transplant may experience recurrent disease in the form of IgAN. Many of the abnormalities of IgA production and handling reported in IgAN are also detected in HSP.

Genetic Basis of IgA Nephropathy

Urine abnormalities increase in frequency among the relatives of IgAN patients, although only in a few pedigrees is IgAN found in multiple generations. One large pedigree has been described in Kentucky, and other large families have been found in Italy and Canada. However, more than 90% of all cases of IgAN appear to be sporadic.

Large worldwide genome-wide association studies have identified genetic modulators that seem to affect the prevalence of sporadic IgAN and modulate its course.^11–13 Variations in major histocompatibility gene loci (HLA-DR, -DQ, -DP and HLA-B) have consistently been identified. Other gene loci are less consistent and include inflammatory mediators (tumor necrosis factor and α-defensin) and gene loci affecting complement factor H.¹⁴

Although uncommon in IgAN (<5% of all cases), one study reports that AKI may be the presentation in up to 27% of patients older than 65 years.¹⁵ AKI develops by three distinct mechanisms. There may be acute severe immune and inflammatory injury with necrotizing GN and crescent formation (crescentic IgAN); this may be the first presentation of IgAN, or it may be superimposed on established, less aggressive disease. Rapid deterioration in IgAN in pregnancy may be caused by crescentic transformation. Alternatively, AKI can occur with mild glomerular injury when heavy glomerular hematuria leads to tubule occlusion by red blood cells (RBCs). Third, especially in elderly patients, chronic IgAN will predispose to AKI from a variety of incidental renal insults (see Chapter 69).

Chronic Kidney Disease

Some patients already have renal impairment and hypertension when they are first diagnosed with IgAN. These patients tend to be older, and they probably have longstanding disease that previously remained undiagnosed because the patient neither had frank hematuria nor underwent routine urinalysis. Hypertension is common, as in other chronic glomerular disease; accelerated hypertension occurs in 5% of patients.

Clinical Associations with IgA Nephropathy

Mesangial IgA deposition is a frequent finding in autopsy studies in chronic liver disease. Although particularly associated with alcoholic cirrhosis, IgA deposition can occur in other chronic liver disease, including that caused by hepatitis B and schistosomiasis. It is thought to result from impaired clearance of IgA by the Kupffer cells, which express Fcα receptors, and hepatocytes, which express the asialoglycoprotein receptor. Clinical evidence of renal disease is more common than previously appreciated, and patients occasionally develop ESRD.

A number of case reports have associated IgAN with human immunodeficiency virus and AIDS. It is not clear whether the polyclonal increase in serum IgA, which is a feature of AIDS, is the predisposing factor.

There are case reports associating IgAN with many other conditions, particularly with a number of immune and inflammatory diseases (Table 23-1). Their relationship to abnormalities of the IgA immune system is not always clear, and some may represent the coincidental development of unrelated but relatively common conditions.

Henoch-Schönlein Purpura

Although most prevalent in the first decade of life, HSP may occur at any age. A palpable purpuric rash, which may be recurrent, occurs on extensor surfaces (Fig. 23-4). There may be polyarthralgia (usually without joint swelling) and abdominal pain caused by gut vasculitis. This may be severe, with bloody diarrhea if intussusception develops. In practice, the diagnosis is made by clinical criteria in the great majority of children, in whom HSP is a self-limiting illness. In adults, clinical features include purpura, arthritis, and gastrointestinal symptoms in 95%, 60%, and 50% of patients, respectively.¹⁶

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