Autoimmune Polyendocrine Syndrome Type 1: History
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Bergithe Oftedal

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells.

  • autoimmune polyendocrine syndrome type 1 (APS-1)
  • autoantibodies
  • B-cells
  • B-cell dependent therapy
  • mouse models of Aire deficiency

1. Introduction

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), is a monogenetic autoimmune disease with an estimated prevalence of 1:100,000 caused by mutations in the autoimmune regulator ( AIRE ) gene [1][2][3][4][5]. Patients usually develop autoimmune manifestations in multiple organs leading to functional impairment, especially of various endocrine glands. APS-1 is diagnosed by the presence of two out of three major clinical components of hypoparathyroidism, chronic mucocutaneous candidiasis (CMC), and primary adrenocortical insufficiency or Addison’s disease. Besides these, multiple other manifestations occur, like primary ovarian insufficiency (POI), autoimmune thyroid disease, type 1 diabetes (T1D), autoimmune gastritis, keratitis, vitiligo, alopecia and enamel hypoplasia are common [1][6]. Alternatively, finding AIRE mutations and specific autoantibodies can be used diagnostically and enable early diagnosis before the main components develop [2][7].

The disease-causing mutations in AIRE are typically inherited in an autosomal recessive manner [8][9], although several heterozygous missense mutations have also been found with a dominant-negative inheritance pattern [10][11]. Overall, more than 130 mutations in AIRE have been identified (Human Gene Mutation Database, www.hgmd.cf.ac.uk , accessed on the 10 of May 2021), many of which cluster in key domains of the AIRE protein [2][8][12][13][14][15][16]. AIRE is mainly expressed in a subset of thymic medullary epithelial cells (mTECs), regulating the expression of 20% of the 20,000 unique tissue-restricted antigens (TRAs) to be presented to the developing T cells during negative selection [17][18][19][20][21]. This transcription factor contributes to the development of thymic Foxp3+ CD4+ regulatory T cells (Tregs) and is crucial for their ability to re-circulate back to the thymus [22][23][24]. In addition, AIRE is necessary for the generation of Tregs ex-thymus [25]. Indeed, APS-1 patients have decreased numbers of Tregs with a modified TCR repertoire compared to healthy individuals, reflecting the abnormal selection of T cells in the thymus [26][27].

Although the pathogenic mechanisms in APS-1 are T cell-mediated, the B cells are important antigen-presenting cells (APCs) that rely on T cell activation for the production of antibodies. They are found in the thymus and are also reported to have some AIRE expression themselves [28][29][30]. We will here look closer into what is known about the B cells in APS-1 patients and AIRE-deficient mouse models, summarize the status quo and the outstanding research questions, and highlight the therapeutic strategies involving B cells in APS-1.

B Cell’s Contribution to APS-1 and Aire Deficiency

Even though the loss of negative selection of T cells in the thymus also affects B cells, both in the thymus and beyond [31][32][33], the role of B cells and their autoantibodies in the pathogenesis of APS-1, as well as their therapeutic potential, is still incompletely known. However, exemplified by B cell depleting therapies, the role of B cells in APS-1 is likely to be more pronounced than previously assumed. One study revealed that treatment with Rituximab, a monoclonal antibody targeting CD20 and leading to B cell depletion, caused a significant reduction of inflammation, infiltration, and tissue destruction in Aire knockout mice [34]. In a study by Popler and co-workers, an APS-1 patient with severe pulmonary disease was treated with Rituximab after the failure of several other immunomodulating therapy approaches, whereupon lung function improved [35]. One could speculate if this effect is tissue-dependent and rely on the observed B cell expansion in the airway mucosal tissue upon antigen exposure [36]. If this also indicates that B cells and T cells contribute differentially to the different disease components remains to be answered. Several human studies have demonstrated recovery of APS-1-related disease components through B cell depletion by Rituximab. This includes studies on patients with isolated autoimmune Addison’s disease where depletion of B cells alone or in combination with depot tetracosactide led to an increase of cortisol and aldosterone levels in a subgroup of participants [37][38].
The autoantibodies produced by B cells are unlikely to be directly pathogenic; rather, they serve a mediating role in the context of an infectious milieu. This is underpinned by experiments showing that sera from AIRE-deficient mice cannot transfer autoimmunity [39]. The autoantibodies are however excellent diagnostic markers, as will be discussed later.

2. Treatment Approaches Targeting B Cells in Autoimmune Diseases

Many current treatment options of autoimmune diseases that focus on B cells include monoclonal antibodies against surface markers which lead to B cell depletion. The most prominent examples are antibodies targeting CD19 (e.g., Obexelimab or Inebilizumab), CD20 (e.g., Rituximab) and CD22 (e.g., Epratuzumab). There are also further promising, but less used surface targets like CD52 (Alemtuzumab), which is efficient for the treatment of multiple sclerosis (MS) [40][41]. CD19 is expressed on B cells of all maturation stages from the pro-B cell stage until late stages of plasma cells, and classical monoclonal CD19 antibodies are for example applied for the treatment of MS (Inebilizumab) [42][43]. Targeting of CD20 leads to a depletion of mature naïve and memory B cells as wells as an inhibition of the development of short-lived plasma cells, although does not have as broad an effect as anti-CD19 treatment. Rituximab is used (partially off-label) for several autoimmune diseases like rheumatoid arthritis, T1D, MS, and systemic lupus erythematosus [44][45][46][47], but is also frequently used for research on B cells in autoimmune diseases. It was found to reduce IgM levels whilst not affecting levels of circulating IgG [48][49]. However, this does not apply to all autoimmune diseases since the reduction in IgG autoantibody titres has also been reported [50]. The antibody-independent effect of Rituximab is thought to be related to the elimination of B cells as APCs leading to a reduced stimulation of T cells [51][52].
Besides classical monoclonal antibody B cell depletion, other approaches can achieve an antigen-specific B cell depletion by redirecting T cells. This approach has been explored in Myasthenia gravis. This is a rare, but often severe, disorder of neuromuscular transmission causing fatigable muscle weakness. It is mostly due to antibodies directed against the AChR, but in a proportion of patients without AChR antibodies, antibodies to muscle-specific tyrosine kinase (MuSK) are found [53]. Like AChR, MuSK is also a membrane protein playing an essential role at the neuromuscular junction. By generating chimeric autoantibody receptor (CAAR) T cells expressing MuSK, MuSK reactive memory B cells were specifically eliminated by the CAAR T cells [54][55]. Other approaches aiming at a selective depletion of B cells are being developed, including the elimination of autoantigen-specific B cells by coupling autoantigens to magnetic nanoparticles and subsequent removal of these autoantigen-specific B cells through extracorporeal filtration [56]. The ultimate goal would be the selective depletion of B cells except for Bregs. Although still in its infancy, CD19-targeted CAR regulatory T cells have been established to suppress B cell pathologies. When injecting these into immunodeficient mice reconstituted with human PBMCs, recovery of graft-versus-host disease was observed [57].
Other treatment approaches focus on neutralizing factors involved in survival or activation of B cells, like BAFF, a proliferation-inducing ligand (APRIL), or transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) [58][59][60]. For example, elevated levels of BAFF have been observed in Sjogren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus. Inhibition of BAFF reduced the symptoms in autoimmune animal models [61][62], as well as in patients [58][59]. Belimumab, a recombinant human monoclonal antibody inhibiting BAFF, has amongst others been evaluated in an international trial involving 448 patients with systemic lupus erythematosus. Belimumab together with standard therapies for lupus nephritis enhanced renal responses and reduced the risk of renal-related events by 50% among patients [63]. There are currently 24 studies with Belimumab registered as “recruiting” or “not yet recruiting” at cliniclatrials.gov, most of which investigate systemic lupus erythematosus. Atacicept is a recombinant fusion protein of the binding portion of the TACI (transmembrane activator and CAML interactor) receptor that neutralizes BAFF and APRIL simultaneously. It is being tested in several autoimmune diseases, including MS and rheumatoid arthritis, but without any noticeable effects so far [64]. Inhibition of B cell activation by blocking the CD40/CD40L interaction of B and T cells was recognized as a possible target in a mouse model of lupus [65][66] but has not yet evolved into human trials.
Biomedicines 09 01274 g001
Figure 1. B cell function and modes of intervention. (A) The effector functions of B cells in the immune system, including the IL-10 producing regulatory B cells. (B) Modes of B cell depletion. Antibodies directed against the B cell-specific markers CD19 and CD20 will deplete all B cells, while chimeric auto-antibody receptor T (CAAR-T) cells and chimeric antibody receptor (CAR)-Tregs can be specifically targeted to autoreactive B cells.

3. Conclusions and Future Perspectives

APS-1 is a severe disease where mutations in the AIRE gene lead to the accumulation of autoimmune manifestations, mainly in the endocrine organs. It is a rare disease but has proved to be a powerful model shedding light on the mechanisms of thymic negative selection of T cells. Although the disease is mainly shown to be T cell-driven, accumulating evidence points to an aberrant immune reaction involving B cells. In particular, peripheral B cell tolerance is compromised resulting in the production of autoantibodies, aberrant T cell activation, and skewing of B cell populations. Modulation of B cell mechanisms has had beneficial effects on autoimmune diseases both in humans and mouse models, highlighting their potential for immunotherapies. They might have a better safety profile than T cell-directed therapies. Combining B and T cell-directed therapies is also a possibility. Nevertheless, detailed information on how the B cell subsets and BCR repertoire behaves in APS-1, functional studies, and explorations on how these cells react to different kinds of immune-modulatory drugs is crucial if we want to target the autoimmune process in APS-1 specifically, for example, to eliminate the self-reactive cells.
Research questions to prioritize:
  • What is the inflammatory cytokine secretion profile of B cells in APS-1 patients?
  • How do B cells in APS-1 patients interact with T cells, DCs, and macrophages, especially with regards to antigen presentation?
  • Is the Breg subset functional in APS-1?
  • Are the hallmark autoantibodies in plasma and sera from APS-1 patients pathogenic?
  • Does B cell depletion therapy improve the main manifestations, and does it impact the interferon profile?
Therapies have also been developed to induce apoptosis of B cell anergy by targeting the BCR or BCR-associated transmembrane signaling proteins like CD79 [67] or target kinases involved in BCR signaling [68], so far only tested in mouse model systems. Potential further targets might include inflammatory cytokines released by the B cells, like IL-6, TNF-α or IFN-α [58], or the lymphotoxin-β receptor to inhibit the formation of ectopic GCs [69] (Figure 1). The use and development of B cell-specific therapies will be interesting to follow and holds the potential to ameliorate several autoimmune disorders, providing treatment beyond the regular substitution medication.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9091274

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