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. Author manuscript; available in PMC: 2022 Mar 1.
Published in final edited form as: Curr Opin Rheumatol. 2021 Mar 1;33(2):197–204. doi: 10.1097/BOR.0000000000000777

Cellular Aspects of the Pathogenesis of Lupus Nephritis

Anthony Chang 1, Marcus R Clark 2, Kichul Ko 2,*
PMCID: PMC7905798  NIHMSID: NIHMS1665348  PMID: 33394604

Abstract

Purpose of review:

Lupus nephritis (LN) is a common severe manifestation of systemic lupus erythematosus. Despite recent advances in therapeutics and understanding of its pathogenesis, there are still substantial unmet needs. This review discusses recent discoveries in these areas, especially the role of tubulointerstitial inflammation (TII) in LN.

Recent Findings:

Non-Caucasian ethnicity is still a major risk and poor prognostic factor in LN. TII and fibrosis have been found to be associated with worse renal outcome but the current LN treatment guidelines and trials are based on the degree of glomerular inflammation. In combination with mycophenolate mofetil, a B-cell-targeted therapy (belimumab) and an calcineurin inhibitor (voclosporin) have shown efficacy in recent LN trials. However, response rates have been modest. While lupus glomerulonephritis results from immune complex deposition derived from systemic autoantibodies, TII arises from complex processes associated with in situ adaptive cell networks. These include local antibody production, and cognate or antigen-induced interactions between T follicular helper cells, and likely other T cell populations, with antigen presenting cells including B cells, myeloid dendritic cells and plasmacytoid dendritic cells

Summary:

Better understanding of the pathogenesis of TII will identify novel therapeutic targets predicted to improve outcomes in our patients with LN.

Keywords: Tubulointerstitial inflammation, lupus nephritis, pathogenesis, adaptive immunity

Introduction

Lupus nephritis (LN) is one of the most common severe manifestations of systemic lupus erythematous (SLE), occurring in up to 50% of SLE patients during the course of the disease (1–6). LN occurs in racial/ethnic minorities at increased frequency in the United States (1, 3, 7), and this trend has also been found in pediatric population (8) as well as in other parts of the world (4, 8). Despite the dramatic renal survival improvement in LN in the 1970’s – 1980’s, this has not changed much since then (9–11). Still up to 50% of LN cases progress to end-stage renal disease (ESRD) (10, 12), and LN, especially when it results in ESRD, is one of the most important predictor of mortality in SLE (6, 13, 14). There is an urgent need to better understand of the disease pathogenesis and develop new therapeutic approaches.

In this review, we discuss the new discoveries in pathogenic mechanisms in LN especially those involving the tubulointerstitial space in kidneys along with recent clinical trials in LN.

Demographic and serological predictors of poor prognosis

In addition to non-Caucasian race/ethnicity, younger age at the time of SLE diagnosis is another risk factor for development of LN (2, 7), along with male sex (6, 15) although this difference between sexes may not be seen in all ethnic groups (16). The majority of LN cases occur either at or in the first 5 years of SLE diagnosis, and the time to LN development is also shorter in non-Caucasian patients (2, 3, 17).

LN patients with non-Caucasian ethnicities especially those with African ancestry have a worse renal prognosis (12, 18, 19), and these findings may be due to both biological and socioeconomic factors (18–20). Serologically, positive anti-SSA antibodies (12), low complements (18) and high serum creatinine (10, 12) correlate with poor renal outcome.

Histology and classification of lupus nephritis

The framework of the LN classification has always centered around glomerular alterations and first was formalized under the auspices of the World Health Organization (WHO) in 1974. Refinements to the classification have occurred in every subsequent decade and the latest 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) version maintains most of the original framework (21). Mesangial immune complex deposition depending on its severity is diagnosed as minimal mesangial (Class I) or mesangial (Class II) LN. The presence of active or chronic glomerular lesions are diagnosed as focal (Class III) or diffuse (Class IV) LN. Membranous (Class V) LN (mLN) can be present in conjunction with class III or IV LN. When membranous and mesangial LN are both present, the class V diagnosis supersedes class II. End-stage (Class VI) LN represents the presence of >90% global glomerulosclerosis.

The following are active glomerular lesions: Glomerular basement membrane (GBM) break, fibrinoid necrosis, cellular or fibrocellular crescent, endocapillary hypercellularity, prominent immune complex deposition in the form of “wire-loop” or hyaline pseudothrombi, or karryorhexis. The rupture of the GBM leads to fibrinoid necrosis and crescent formation. The remaining active lesions are related to immune complex deposition or the inflammatory response to these glomerular immune complexes.

Given that the LN classification categories are fairly crude, the addition of the National Institute of Health (NIH) activity and chronicity indices (AI and CI) provides additional granular information regarding the degree of active and chronic lupus renal disease, which is pertinent for focal and diffuse LN (21). For example, a LN biopsy with 5% or 45% active glomerular lesions would both be considered focal LN. Likewise, a biopsy with 50% compared with 90% active glomerular lesions would both be considered diffuse LN.

The NIH AI considers the following six parameters: Cellular and/or fibrocellular crescents, fibrinoid necrosis, wire-loop and/or hyaline “thrombi,” neutrophils/karyorrhexis, and interstitial inflammation. These individual parameters are assessed and the extent of glomerular involvement is determined using these categories of 0%, 1–24%, 25–50%, or >50%, which are assigned a semiquantitative score of 0 – 3 points. The cellular/fibrocellular crescent and fibrinoid necrosis scores are both multiplied by two for a score of 24 total points. The NIH CI assesses four parameters: Global glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis and a sum of these four categories (0 – 3 points for each) is a score of 12 total points.

The extent of activity reflects ongoing injury that may be responsive to therapeutic intervention. Chronicity indicates scarring and irreversible damage that is unlikely to respond to therapy.

The prognostic importance of tubulointerstitial inflammation and tubulointerstitial scarring

Tubulointerstitial inflammation (TII) repeatedly has been demonstrated to be an important pathologic parameter, but remains overshadowed by the glomerulocentric approach to the clinical management of LN. Hill and colleagues first identified interstitial inflammation as “one of the pivotal variables” in LN (22) which has been confirmed in several more recent studies. In fact, we found that TII was more predictive than the glomerular injury (23).

The degree of interstitial fibrosis and tubular atrophy (IF/TA) is the pathologic parameter that best predicts clinical outcomes in LN (23–25), and this is true for many renal diseases. In fact, tubulointerstitial scarring was more important that the other three glomerular parameters that were ultimately included in the Oxford IgA nephropathy classification. Of note, interstitial inflammation was also a significant pathologic parameter, but did not provide any information beyond tubulointerstitial scarring so it was eliminated from the final classification (21). While this was implemented for practical purposes, the omission of TII in IgA nephropathy has a similar inadvertent effect of shifting attention back to glomeruli.

African ancestry which is one of the most important predictors of poor renal outcome has been shown to be associated with presence of moderate to severe TII which in turn correlates with presence of IF/TA (23, 26). Therefore, current classifications largely fail to capture the prognostically important histological features which are especially frequently found in LN patients with African ancestry.

Recent clinical trials with lupus nephritis

Treatment of LN has made incremental progress in the past few decades. Despite the tubuloinsterstitial process being an important prognostic factor, patients with LN continue to be stratified based on the glomerulocentric ISN/RPS classification criteria (21) for therapeutic strategies to be determined (27, 28). For proliferative LN (pLN, Classes III and IV) either with or without membranous LN (mLN, Class V), the induction regimen traditionally had involved intravenous cyclophosphamide (CYC) with glucocorticoids based on the NIH trials (29); however, in the past two decades, low dose CYC and mycophenolate mofetil (MMF) have emerged as non-inferior but safer alternatives (30–33). In fact, MMF has shown higher efficacy over monthly intravenous CYC in pLN patients, especially in groups mostly comprised of African ancestry or Hispanic ethnicity (31, 32). MMF and azathioprine are both the mainstay medications for pLN maintenance after induction (28, 34, 35) whereas MMF has shown superiority over azathioprine in one international study (34).

Pure mLN cases have often been included in small numbers in the previous large trials for LN (29–33), and thus, data for pure mLN treatment are limited. Both the American College of Rheumatology (ACR) and European Union League Against Rheumatism (EULAR) recommend MMF along with glucocorticoids as an induction therapy for pure mLN (27, 28). Of note, cyclophosphamide, MMF and azathioprine are all used as off-label therapies in LN.

Numerous other therapies have been studied in LN and most failed to show positive results (36, 37). Despite many setbacks in recent years, different medications especially in combination against various targets are rigorously being researched, and are starting to demonstrate promising results. Tacrolimus, a calcineurin inhibitor, either alone or in combination with MMF has shown efficacy in LN in Chinese patients (38, 39). Voclosporin, another calcineurin inhibitor which is not yet approved by the United States Food and Drug Administration, in combination with MMF showed superiority over MMF alone in phase 2 and 3 multi-ethnic trials (40, 41). Despite the failure of rituximab, a monoclonal anti-CD20 antibody in a large randomized controlled trial for LN (42), another B-cell-targeted therapy, belimumab which targets B-cell activating factor showed positive results in a phase 3 trial in combination with MMF (43). While the successful results from these novel approaches are encouraging, the renal response rates are still well below 50%, and their efficacy is unclear in patients of African ancestry due to the small size of this cohort in the trials (40, 41, 43). Therefore, there are great unmet needs in LN research.

Lupus glomerulonephritis as a manifestation of systemic autoimmunity

LN is often equated with glomerulonephritis (GN). Canonically, lupus GN is driven by immune complex-mediated inflammation in which autoantibodies and preformed immune complexes (ICs) deposit in glomeruli and cause inflammation. Much work has focused on the role of anti-double stranded (ds) DNA antibodies. Indeed, serum titers of anti-dsDNA antibodies correlate with proliferative GN (44). Elegant studies have demonstrated that anti-dsDNA antibodies can form ICs with DNA-wrapped nucleosomes, and these can then directly deposit in glomeruli (44–46). Alternatively, anti-dsDNA antibodies can directly bind glomeruli. This could be because of cross-reactivity, or recognizing DNA bound to collagen or chromatin fragments bound to lamin and collagen (45). Anti-dsDNA antibodies have been purified from nephritic kidneys (47, 48). Importantly, infused anti-dsDNA antibodies can bind glomeruli and induce GN in non-autoimmune mice (49, 50). This provides a direct pathogenic link between anti-dsDNA antibodies and GN. Interestingly, not all anti-dsDNA antibodies are likely to be nephritogenic (51). Therefore, there must be specific biophysical features, beyond just binding dsDNA, that confer pathogenicity.

More recent work has implicated other immunological mechanisms in lupus GN. Among these are neutrophils and their ability to extrude DNA/protein nets (52–54). Oxidized mitochondrial DNA released by neutrophils and other cells, also drives local inflammation (55).

Furthermore, lupus is associated with increased circulating levels of an activated subset of neutrophils, low density granulocytes (LDGs), that generate nets (NETosis) more easily than other neutrophil populations (56, 57). These LDGs, presumably, provide for abundant nets that drive systemic inflammation and breaking of both B and T cell tolerance. Neutrophils respond to multiple inflammatory stimuli, including interferons (IFN) and autoantibodies, which can make them more likely to undergo NETosis. Therefore, it is unclear if neutrophil dysregulation is a secondary manifestation, or primary cause, of lupus. They might be more important is amplification of systemic inflammation rather than in initiating disease. Furthermore, in mice, neutrophils can also repress inflammation and B cell activation (58) and neutrophils play multiple homeostatic roles (52). This suggests the contributions of neutrophils to lupus might be complex.

Recent transcriptomic studies of peripheral blood have revealed seven different lupus subsets (59). Most notably, a predominance of neutrophil transcripts, a neutrophil signature, correlated with active nephritis. However, neutrophils are not a characteristic histologic feature of LN. Indeed, they are only occasionally seen in very inflamed glomeruli and are essentially absent from the tubulointersititum (discussed below). Therefore, it is likely that neutrophilia and NETosis are feature of systemic autoimmunity that contribute to a general inflammatory state and loss of systemic tolerance.

There is also a relationship between lupus activity, titers of anti-dsDNA antibodies and circulating levels of T follicular helper (Tfh) cells (60, 61). Tfh cells are specialized for providing help to B cells in germinal center (GC) light zones (62). Indeed, it has been demonstrated in mice that Tfh cell help limit and direct somatic hypermutation and affinity maturation (63). In human peripheral blood, at least three different Tfh-like populations have been detected that differ in their in vitro activities (64). However, none of these populations are directly comparable to those Tfh cells in GCs. While correlated with lupus activity, Tfh cells are not observed in glomeruli (65). However, as discussed below, they might play an important role in TII.

Indeed, for all the peripheral immune mechanisms that have been associated with lupus GN, the pathology in glomeruli is rather nonspecific and consists of mostly effector T cells and macrophages. We propose this reflects systemic autoimmunity and a linear pathogenic model. In other words, neutrophils, Tfh cells, pDCs and associated processes contribute to GN by breaking tolerance and inducing inflammation. Then, the products of autoimmunity and inflammation are exported to glomeruli in the form of T cells and antibodies. In this model, there are no amplification loops that involve those processes active in glomeruli.

Tubulointerstitial inflammation associated with in situ adaptive cell networks.

In contrast to glomerular inflammation, inflammation in the tubulointerstitium is complex and in many cases organized into structures reminiscent of those observed in secondary lymphoid organs (66). In an earlier study, closely packed T:B aggregates were observed in about half of patients while five of seventy had GC-like structures including clearly formed light and dark zones, follicular dendritic cell networks and discrete areas of proliferating B cells (67). Indeed, sampling of these GCs using laser capture microscopy and extensive sequencing revealed strong clonal expansion and ongoing somatic hypermutation. Given that these were diagnostic needle biopsies, providing a very small sample size, we likely underestimated the prevalence of tertiary lymphoid neogenesis. These data clearly demonstrate in situ antigen-driven selection which has not been observed, and indeed is unlikely to occur, in inflamed glomeruli.

Furthermore, it is likely that a restricted number, and classes of antigens, drive in situ B cell selection in lupus TII. Indeed, cloning and expressing antibodies expressed by clonally expanded intrarenal B cells revealed that the majority expressed antibodies that bound cytoplasmic, ubiquitously expressed antigens (68). Among these, most directly bound vimentin. In contrast, across eight patients we did not find clonal expansion of B cells expressing anti-dsDNA antibodies.

Vimentin is an intermediate cytosolic filament and has been thought to be a structural protein. However, mice with a deletion in the gene encoding vimentin are phenotypically normal (69). Furthermore, vimentin is strongly upregulated by some inflammatory and injured cells. Indeed, vimentin is highly expressed throughout the inflamed lupus tubulointerstitium (68). In activated macrophages, vimentin is secreted and presented on the cell surface suggesting roles other than that of a structural protein (70). Furthermore, vimentin might be a pro-inflammatory molecule sensed by Dectin-1 (71). These data suggest that tolerance is broken in situ to molecular patterns of inflammation. This provides a potential in situ feedforward mechanism in which inflammation elicits local adaptive immunity leading to antibody deposition and more inflammation.

In a cross-sectional cohort, serum anti-vimentin antibodies (AVAs) correlated with TII severity (72). Furthermore, high-titer AVAs in LN patients predict a poor response to both MMF and MMF plus rituximab therapy. Interestingly, AVA serum titers did not correlate closely with other autoantibodies and, in contrast to anti-dsDNA antibody titers, did not change substantially with therapy. These data suggest that serum AVAs provide a measure of TII in the periphery that is prognostically meaningful and different than that provided by other antibody specificities. We would propose that while serum anti-dsDNA antibodies reflect mechanisms relevant to GN, AVAs capture a TII pathogenic process. In the periphery, selection is for antibodies to DNA or RNA protein complexes. Work in mice has shown these specificities to be dependent on toll-like receptor signaling (73). In contrast, vimentin is a protein antigen to which B cell responses should be fully dependent upon T cell help.

Indeed, in addition to B cells, there are Tfh cells within the inflamed tubulointerstitium (65). These Tfh cells are mature, with high levels of IL-21 indicating they have recently provided productive help to B cells. Furthermore, these intrarenal Tfh cells are in intimate contact with B cells forming complex immunological synapses consistent with ongoing cognate help. These data suggest that in addition to recognizing antigen, intrarenal B cells are getting critical costimulation from cognate T cells. These two signals are predicted to provide the necessary stimulation for full in situ activation and differentiation. Indeed, our analysis indicates that the T:B aggregates that are often observed histologically represent collections of Tfh cells providing help to B cells. Interestingly, within these aggregates, there is relatively little proliferation (unpublished observation). Rather, proliferation is seen within the intrarenal plasmablast pool. We propose that there is selection within T:B aggregates for cells that subsequently differentiate into plasmablasts.

Different Tfh cell populations have been identified in lupus. Notable is a population of T cells in peripheral blood, and in the inflamed tubulointerstitium, that can activate B cells via IL-10 and succinate (74). In contrast to canonical Tfh cells, these cells do not rely on IL-21 for B cell activation. In rheumatoid synovium and the blood of lupus patients, peripheral T helper (Tph) cells have been described which differ from Tfh cells in the chemokine receptors they express and possibly in their underlying molecular programming (75, 76). Therefore, the heterogeneity of T cell helper pools across blood and tissue, and their relative importance in activating B cells in different diseases, remains to be understood.

SLE is thought to be the canonical B cell-driven systemic autoimmune disease and therefore much effort has been directed to defining how autoreactive B cells are selected and activated. However, recent single cell (sc) RNA-Seq experiments have revealed great complexity in the cells infiltrating the lupus kidney including populations of CD8+ T cells, natural killer cells, dendritic cells, macrophages and pDCs (77). In another related study that captured both immune cells and renal tubular/stroma cells, it was clear that important ligand/receptor pairs mediate communication between immune cells and their environment (78). This complex web of interactions likely drive in situ inflammation and fibrosis. These studies were done on relatively few biopsies and the data were reported in aggregate. We do not know if all cells are present in all biopsies. Furthermore, we do not know the spatial or functional relationships between these different cell populations. Unraveling how these cells independently, and as part of immune cell networks, mediate TII and fibrosis will almost certainly reveal new therapeutic targets.

These scRNA-Seq studies also provided insights into the phenotypes of the B cells infiltrating the inflamed kidney. Notably, double negative (IgD-CD27-) B cells appeared common (77). These cells have been studied in the periphery, accumulate with age and have been associated with autoimmunity (79, 80). One of the markers they express is the transcription factor, T-bet, which most commonly lies downstream of Toll-like receptor activation (81). Therefore DN cells likely arise from activation pathways commonly implicated in lupus including those involved in the generation of anti-dsDNA and anti-ribonucleoprotein antibodies. However, the antibody repertoire of these DN cells is not known. It will be important to resolve intrarenal B cell heterogeneity and to determine if DN cells, or other in situ B cell populations, express anti-vimentin antibodies.

The most common lymphocyte population in the kidney are CD4+ T cells. While some of these are Tfh cells, the majority are not (unpublished observation). The role of these non-Tfh CD4+ T cells is still not clear. However, at least one mechanism by which they are activated in situ has been identified. pDCs are canonically primary sources of IFN alpha (IFNa). However, it is now clear that pDC subsets can present antigens (82). Interestingly, it appears that antigen presentation and IFNa secretion by pDCs are mutually exclusive states; at any one time, a pDC does one or the other. However, single cell studies have demonstrated that the same cell can, over time, do both functions (83). In recent studies, we have used confocal microscopy and deep machine learning to demonstrate that pDCs are important in situ antigen presenting cells (APCs) in LN (84). Indeed, in most patients studied, they were more important APCs than classical CD11c+ dendritic cells. Interestingly, these cells did not express markers of antigen presenting pDCs in the periphery. Therefore, the relationship between peripheral and intrarenal pDCs is unclear. Furthermore, how in situ, pDCs form different functional populations is not known. There is a great deal to learn about the in situ APCs in LN.

The above results demonstrate that many cell types, and many immunological mechanisms, mediate lupus TII. Furthermore, they appear to be quite different than those associated with lupus GN. This includes both the cells involved and the antigen specificities driving lymphocyte selection in each renal compartment. At the time of clinical presentation, glomerular and TII are markedly different. However, inflammation in each compartment might arise from similar initiating mechanisms. Indeed, we propose that a systemic autoimmune diathesis is likely required for TII to develop. Furthermore, inflammation in the two renal compartments could be functionally related. Indeed, tubulointerstitial hypoxia, which has been related to glomerular inflammation (66), is a feature of both human and mouse lupus TII (85).

The vast majority of lupus therapies are predicated on a model of systemic autoimmunity whose relevance might be limited to GN. To reveal new therapeutic targets, that are likely to alter the natural history of LN, it will require identifying important intrarenal mechanisms driving TII, fibrosis and ultimately renal failure.

Conclusion

Despite the recent scientific advances in LN, there is still substantial room for improvement. Currently, the focus of LN, both in clinical trials and mechanistic studies, is still focused on lupus GN rather than TII. As described in this review, there is a tale of two pathogenic mechanisms in LN, one involving the glomeruli and systemic autoimmunity, and the other involving the tubulointersitium and in situ local adaptive immunity. Understanding the pathogenesis of TII and tubulointerstitial scarring will reveal new and better therapeutic targets which will diminish mortality and improve the quality of life for those afflicted with LN.

Key points.

  • A B-cell targeted therapy, belimumab and calcineurin inhibitor, voclosporin have shown success in recent clinical trials for lupus nephritis.

  • Tubulointerstitial inflammation and fibrosis are poor prognostic factors in lupus nephritis.

  • Tubulointerstitial inflammation is associated with in situ adaptive immunity which is distinct from systemic autoimmunity which is related to glomerular process in lupus nephritis.

Acknowledgments

Financial support and sponsorship

MRC gets support from grants from the National Institute of Health (U19 AI082724) and Department of Defense (LRI180083).

Financial Disclosures: Marcus R Clark gets grant supports from the NIH (U19 AI082724) and Department of Defense (LRI180083) but none relevant to this manuscript.

Footnotes

Conflicts of interest

AC is a consultant and on the speaker’s bureau for Alexion Pharmaceuticals Inc.

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