Journal of Clinical Medicine Review History of IgA Nephropathy Mouse Models Batoul Wehbi 1, Virginie Pascal 1, Lina Zawil 1, Michel Cogné 2 and Jean-Claude Aldigier 1,* 1 Immunology Department, UMR CNRS 7276 INSERM 1262, Limoges University, 87032 Limoges, France; [email protected] (B.W.); [email protected] (V.P.); [email protected] (L.Z.) 2 Immunology Department, EFS Bretagne, INSERM 1236, Rennes 1 University, 35000 Rennes, France; [email protected] * Correspondence: [email protected] Abstract: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this Citation: Wehbi, B.; Pascal, V.; manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable Zawil, L.; Cogné, M.; Aldigier, J.-C. History of IgA Nephropathy Mouse contribution to understanding the disease. Models. J. Clin. Med. 2021, 10, 3142. https://doi.org/10.3390/ Keywords: IgA nephropathy; IgA; kidney mesangium; mouse model jcm10143142 Academic Editors: Hitoshi Suzuki and Jan Novak 1. IgAN Epidemiology The true prevalence of IgAN cannot be exactly determined. IgA deposits on the kidney Received: 6 May 2021 are indeed frequent in asymptomatic patients and were reported in 16.1% of a population of Accepted: 9 July 2021 kidney donors in Japan [1]. However, the overt disease can evolve to a rapidly progressive Published: 16 July 2021 glomerulopathy (Figure1). Since the diagnosis of IgAN requires a kidney biopsy, available data only refer to cases recorded after this procedure. The prevalence of IgAN varies widely Publisher’s Note: MDPI stays neutral across different geographic regions and ethnic groups [2]: IgAN is most prevalent in East with regard to jurisdictional claims in Asian people (with more than 40% of biopsy cases in Japan), followed by Caucasians and published maps and institutional affil- African individuals (respectively with about 25% and less than 5% of biopsy cases) [3]. iations. This disparity in population distribution can be attributed to the different health screening policies as well as several genetic and environmental factors. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 3142. https://doi.org/10.3390/jcm10143142 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 3142 2 of 11 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 11 FigureFigure 1.1. IgANIgAN represent represent the the emergent emergent part part of of the the IgA IgA deposition deposition iceberg iceberg with with a heterogeneity a heterogeneity un- underscoringderscoring the the multifactorial multifactorial pathogenesis pathogenesis of ofthe the disease. disease. 2.2. IgAN:IgAN: ClinicalClinical andand HistopathologicalHistopathological PresentationPresentation ThereThere isis significantsignificant heterogeneityheterogeneity inin thethe clinicalclinical manifestationsmanifestations ofof IgANIgAN sincesince eveneven healthyhealthy subjectssubjects withwith nono clinicalclinical signssigns ofof IgANIgAN maymay havehave mesangialmesangial deposits.deposits. ByBy contrast,contrast, forfor thosethose patientspatients developingdeveloping glomerulopathyglomerulopathy withwith proteinuriaproteinuria and/orand/or hematuria,hematuria, one-one- thirdthird ofof thethe casescases willwill progressprogress toto endend stagestage renalrenal diseasedisease (ESRD)(ESRD) [[4].4]. HighHigh bloodblood pressurepressure maymay alsoalso be an indicative indicative sign sign of of IgAN; IgAN; it itis isalways always present present as assoon soon as askidney kidney failure failure be- begins.gins. In Inpatients patients presenting presenting such such features, features, renal renal biopsy biopsy is the is the only only method method to confirm to confirm di- diagnosis.agnosis. The The anatomo anatomo-pathological-pathological study study of ofrenal renal biopsy biopsy specimens specimens reveals reveals mesangial mesangial le- lesions:sions: mesangial mesangial matrix matrix expansion expansion and and hypercellularity sometimes associated withwith aa mesangialmesangial cellcell proliferationproliferation withwith possiblepossible endo-endo- oror extra-capillaryextra-capillary proliferationproliferation oror eveneven significantsignificant glomerularglomerular inflammationinflammation andand crescentcrescent formation.formation. OtherOther lesionslesions cancan alsoalso bebe identified:identified: segmentalsegmental sclerosis,sclerosis, tubulartubular atrophy,atrophy, andand interstitialinterstitial fibrosisfibrosis [5[5].]. TheThe analysisanalysis ofof thesethese differentdifferent lesionslesions makesmakes itit possiblepossible toto establishestablish thethe OxfordOxford predictivepredictive scorescore forfor diseasedisease progressionprogression [[6].6]. Immunofluorescence Immunofluorescence on on biopsies biopsies reveals reveals the the presence presence of ofmore more or orless less diffuse diffuse granular granular or or filamentous filamentous IgA IgA deposits deposits in in the the form form of “dead“dead trees”trees” oror “nail“nail strokes”strokes”[ [5].5]. TheThe presencepresence ofof lambdalambda andand kappakappa lightlight chainchain depositsdeposits hashas beenbeen reportedreported [[7].7]. IgAIgA deposits deposits most most often often co-localize co-localize with with C3, C3, sometimes sometimes with with IgG IgG and and IgM IgM [3]. Moreover,[3]. Moreover, the presencethe presence of deposits of deposits at the at the level level of singleof single glomeruli glomeruli is is sufficient sufficient to to make make the the diagnosis diagnosis [[5]5].. 3. Enigmatic Functions of IgA 3. Enigmatic Functions of IgA IgA antibodies (Ab) are exceptionally abundant at mucosal surfaces; more than 80% IgA antibodies (Ab) are exceptionally abundant at mucosal surfaces; more than 80% of mammalian Ab secreting plasma cells reside in the gut and secrete IgA. Notably, with of mammalian Ab secreting plasma cells reside in the gut and secrete IgA. Notably, with the exception of germ-free animals or germ-free mucosal tissues, these antibodies arise the exception of germ-free animals or germ-free mucosal tissues, these antibodies arise prominently during homeostasis in the absence of overt inflammation and immunization. Consistently,prominently during the influence homeo ofstasis super in the antigens absence expressed of overt inflammation by bacteria present and immunization. early in the intestinalConsistently, flora the has influence recently of been super demonstrated antigens expressed [8]. Despite by bacteria its abundance, present early the in in vivo the specificityintestinal flora and dualhas recently functions been of IgAdemonstrated still remain [8]. somehow Despite enigmatic,its abundance, although the in these vivo antibodiesspecificity and appear dual as functions major players of IgA instill the remain functional somehow balance enigmatic, opposing although tolerance these and an- inflammationtibodies appear in as the major context players of mucosal in the functional immunity balance and as opposing important tolerance organizers and inflam- of the microbiotamation in the composition context of mucosal in healthy immunity subjects and [9]. as At important the gut-associated organizers lymphoidof the microbiota tissue (GALT)compositio level,n in there healthy are two subjects distinct [9]. aspects At the of gut humoral-associated immunity: lymphoid first, tissue the mechanisms (GALT) level, of J. Clin. Med. 2021, 10, 3142 3 of 11 humoral homeostasis against commensal bacteria seem to involve the so-called “natural IgA”. Their repertoires are almost germline with slightly mature variable regions [10]. These IgA share an interspecies reactivity because they are often polyreactive and partly produced by B-lymphocytes in a T-independent context. Second, during the local immune response induced by pathogens, protective high affinity IgA are produced in the mucosa-associated lymphoid tissue (MALT) germinal centers. This T-dependent response is similar to that of a general response establishing specific immunity as effective as a response