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Rheumatology Advance Access originally published online on May 31, 2008
Rheumatology 2008 47(8):1111-1113; doi:10.1093/rheumatology/ken202
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Germinal centre-like structures in Wegener's granuloma: the morphological basis for autoimmunity?

A. Mueller1, K. Holl-Ulrich2, P. Lamprecht1 and W. L. Gross1

1Department of Rheumatology and 2Institute of Pathology, University of Luebeck, Luebeck, Germany

Correspondence to: A. Mueller, Department of Rheumatology, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany. E-mail: mueller{at}mail.uni-luebeck.de

Wegener's granulomatosis (WG) shows a unique dual morphology in comprising a vasculitis as well as extravascular granulomatous inflammation. Together with the much rarer Churg–Strauss syndrome, WG is the only primary systemic vasculitis that features a salient extravascular inflammatory component. While the pathophysiology of ANCA-induced endothelial vessel wall damage has been well studied (for review see [1]), more recent data described the formation of lymphatic follicles in granulomatous lesions and their potential role for the generation of ANCA against Wegener's autoantigen proteinase 3 (PR3-ANCA) [2, 3]. Further, an intricate interplay between cells and molecules of the innate and adaptive immune response resulting in chronic inflammation has been elucidated for WG, lately [4–7]. From these and other findings, a pathogenetic and pathophysiological scenario emerges, in which multiple steps of the immune pathology leading from granulomatous, autoantibody-negative to vasculitic, autoantibody-positive WG are being dissected [8, 9].

Morphological spectrum of Wegener's granuloma

The concept of WG starting as a localized, often ANCA-negative disease with predominant ENT involvement and later progressing to a generalized, ANCA-positive vasculitis has been supported by larger studies and a case report [10–13]. During the pathogenesis of WG, granulomas, mostly within the upper and lower respiratory tract, are the first morphological hallmark in the localized phase. WG granulomas (Fig. 1) are typically very poorly defined epitheloid cell granulomas or scattered epitheloid cells and giant cells within a dense mixed inflammatory background containing dispersed lymphocytes, plasma cells, PMNs and eosinophils. Within the granulomatous inflammation, neutrophilic microabscesses and necrosis may develop, eventually leading to the characteristic geographical necrosis [14] with palisading granulomatous inflammation [15, 16]. Eventually, these mechanisms may lead to severe and extensive local destruction of nasal tissues and bones (Fig. 1) as well as adjacent anatomical structures such as the orbital bones and the meninges [7].


Figure 1
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  		FIG. 1. WG in sinonasal mucosa (H&E, x 100): characteristic ill-defined Wegener's granuloma with epitheloid cells and several giant cells (arrowheads), at the right inflammatory destruction of adjacent bone (B) by pannus-like tissue (asterisks). Typical dense lymphoplasmocytic inflammatory background with beginning formation of follicular structures (dotted circles).

 

Germinal centre-like structures in Wegener's granuloma: inducing and sustaining autoimmunity?

A number of human autoimmune diseases (e.g. RA, SS) feature the development of the so-called ectopic or tertiary lymphatic organs/structures in non-lymphoid tissues [17]. Such structures could develop to become a place of autoantibody generation, i.e. anti-Ro/SSA and anti-La/SSB antibodies in SS [18]. Intriguingly, in RA lymphoid follicles with germinal centres and granuloma formation, associated with parameters such as RF production, have been found in the inflamed synovia and rheumatoid nodules [19, 20]. Thus, the question arises whether WG also represents an autoimmune disease, where such germinal centre-like structures develop within the chronic inflammation of the respiratory tract. Indeed, similar to rheumatoid synovitis [21], different lymphocytic phenotypes are observed in the granulomatous lesions of WG, ranging from diffusely infiltrating cells towards aggregated T and/or B lymphocytes without follicular dendritic cells (DCs) to germinal centre-like structures with follicular DCs (Fig. 2A–C). In addition, WG granulomas contain clusters of PR3+ cells (neutrophils, monocytes) surrounded by antigen-presenting cells (e.g. CD208+ DCs) as well as effector T cells, expressing the activating receptor NKG2D [6]. These NKG2D + cells could bind to cells expressing the NKG2D ligand, MIC (MHC class I related chain) [22], promoting a self-perpetuating inflammatory and autoimmune response in the tissue.


Figure 2
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  		FIG. 2. (A) Clustering of CD20+ B cells in nasal WG granuloma (x 200) (B) Differentiation of lymph follicles as shown by CD35-expressing follicular DCs in nasal WG granuloma (x 200) (C) Aggregation of CD3+ T cells in nasal WG granuloma (x 200) (D) IL-17D+ cells in nasal WG granuloma (reprinted with permission from Springer Verlag [49], copyright 2008).

 
Since the tertiary lymphatic structures can develop during infectious conditions [17], one of the open questions is if the germinal centre-like structures in the WG granuloma might be initially formed in order to eliminate an infectious pathogen. A viral infection induced in an animal model of autoimmune diabetes not only aggravated the disease, but is accompanied by neoformation of lymphoid structures in the target organ [23]. For WG, it is postulated that exposure to an unknown aetiological agent, potentially combined with a certain genetic background (for review see [24, 25]), will lead to a break of tolerance against PR3. Nasal carriage of Staphylococcus aureus has long been discussed as such a pathological event [26]. Recently, one of the S. aureus superantigens, toxic shock syndrome toxin 1 (TSST-1), has been demonstrated as a risk factor for disease relapse in WG [27]. Therefore, it should not be ruled out that an infection can at least participate in the granulomatous reaction of WG.

In summary, the formation of germinal centre-like structures in WG granulomas may be important for the initiation and maintenance of the autoimmune response against PR3. Nonetheless, from granuloma to vasculitis, a number of issues remain to be determined, especially: is a break of tolerance against PR3, possibly via molecular mimicry, and the initial autoantibody response taking place in the granuloma and secondly, which molecules and cells are the relevant contributors?

Exogenous and endogenous factors governing granuloma formation and autoimmunity to PR3 in WG

In the peripheral blood of patients with WG as well as with RA, a phenotype of high membrane PR3-expressing PMN has been described as being predominant over less membrane PR3-expressing phenotypes [28]. Additionally, a number of cellular mechanisms such as activation by pro-inflammatory cytokines [29] or apoptosis [5, 30] have been described, leading to more translocation of intracellular PR3 to the surface of PMN and/or to release of PR3 into the microenvironment. A polymorphism in the promoter region of PR3, associated with WG, presents yet another possibility of an increased expression of PR3 [31]. Moreover, tissue studies showed that PR3+ PMN represent a large, if not the largest cellular population within the granulomatous lesions of the respiratory tract [32, 33]. Therefore, strongly elevated cellular expression of PR3 in WG is likely and offers many opportunities for recognition by immune cells (like DCs), eventually not silencing but enhancing a pro-inflammatory pathway. Indeed, it has been demonstrated that PR3 exhibits pro-inflammatory properties via specific activation of pro-inflammatory cytokines [34]. Together with necrosis (Fig. 1), involving PR3+ PMN, these features could support the selection of PR3 as an autoantigen in the nasal mucosa [35]. An analysis of macrophages and multinucleated giant cells in WG granulomas revealed activation, indicative of active local antigen processing and presentation as well as maturation, leading to ‘organized’ granulomas. Furthermore, it was detected that these scavenging cells are not able to remove all tissue debris [5, 36], which may favour the development of necrotic areas. As already mentioned, different variants of professional antigen-presenting cells, e.g. CD35+ follicular DCs can be found in the WG granuloma as well, but their functions are still under investigation. It seems not unlikely that immature DC migrating into the granulomatous inflammation can mature through interaction between the protease-activated-receptor-2 (PAR-2) and PR3 [4]. PAR-2-expressing alveolar macrophages have been observed in granulomatous lesions of the lung, but their role remains to be evaluated [37]. While in most cases a dispersed concomitant T-lymphocytic infiltrate can be detected [38], some patients develop well-defined B-lymphocytic follicular structures with similarities to a germinal centre [36]. This is in aggreement with our data, showing a clustering of B cells in nasal and lung granulomas of WG together with signs of B-cell selection and affinity maturation [2]. We observed several cases of differently mutated members of one B-cell clone, indicative of clonal expansion and intraclonal diversification within the granulomatous lesions [3]. Besides similarities to other autoimmune diseases with regard to the presence of focal accumulations of T and B cells in non-lymphoid tissues, WG patients showed a functional polymorphism in the intracellular tyrosine phosphatase PTPN22, which could lead to a lowered threshold for T-cell activation [39]. Previous findings demonstrated that the cytokine profile of granuloma T cells differs between localized and generalized WG. In localized WG, the granuloma T cells displayed a strong expression of IFN-{gamma} as well as of the chemokine receptor CCR5 [40–42]. In generalized WG, a shift towards IL-4+ Th2-like cytokine pattern by granuloma T cells has been demonstrated [43]. Furthermore, we detected TNF-{alpha}-producing granuloma T cells and the majority of these T cells represents a CD28– phenotype that is suggestive of effector T cells [44, 45]. Recently, we could show that the activating NK receptor NKG2D is anomalously and preferentially expressed on circulating CD4+CD28– T cells in WG. NKG2D+ cells and cells expressing its ligand MIC are found in WG granulomas in vicinity to clusters of PR3+ cells. Moreover, the pro-inflammatory cytokine IL-15 is expressed in the WG granuloma [6]. An imbalance in favour of pro-inflammatory cells or molecules, including the acquisition of NK-like ‘innate’ properties of NKG2D+ effector T cells as well as an altered regulatory T-cell function could sustain the granulomatous inflammation and further perpetuate the pathology in WG. Last but not least, two studies yielded a strong association of WG with the HLA-DPB1 locus [46]. Since berylliosis, a disease characterized by granulomatous inflammation, also exhibited an association with HLA-DP alleles [47] this might indicate a genetic influence on granuloma formation and persistence.

However, there are many open questions left. Why are prominent lymphatic structures not detectable in all patients with generalized disease? How is this modulated by immunosuppressive therapy? Does the Th1-like cytokine profile in the granulomatous lesion of localized WG have a ‘limiting effect’ for further disease extension, similar to a granuloma in tuberculosis that contains and kills mycobacteria? Another question that has yet to be answered is the role of Th17 cells in WG and in the granuloma. Th17 cells have been reported as highly pro-inflammatory and a major player of tissue destruction, especially in murine models of autoimmune diseases [48]. Interestingly, we detected IL-17 expressing cells in WG granulomas (Fig. 2D; [49]). A thorough evaluation of cytokine profiles in WG granuloma might be of help in explaining, why some patients remain in the purely granulomatous localized phase for years without showing systemic vasculitis, while in others WG rapidly progresses from the localized phase to a fulminant generalized vasculitis.

Thus, future investigations will have to further elucidate molecules and mechanisms that have been described as relevant for the development of germinal centre-like structures in autoimmune diseases as well as for tissue destruction. This includes a detailed characterization of the different stages of the granuloma organization during the course of the disease as well as the examination of molecular and cellular interactions between (auto)antigen-presenting cells and T and B lymphocytes in WG granulomas.

Acknowledgements

Our current studies are funded by the German Research Society (KFO170, TP04) and the Association for the advancement in research of rheumatic diseases e.V. Bad Bramstedt.

Disclosure statement: The authors have declared no conflicts of interest.

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Accepted 16 April 2008


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