ACIGDSLE

Regulation and function of IgD in systemic lupus erythematosus

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 Obiettivo del progetto (Objective)

'Anti-nuclear antibodies (ANAs) are the most common types of autoantibodies in SLE. Elevated levels of ANAs belonging to the IgD class have long been observed in SLE patients, reflecting dysregulation of the IgD compartment, but the significance of this dysregulation in SLE pathogenesis is completely unknown. IgD in healthy individuals reacts more frequently with nuclear antigens than IgG, the antibody class well-recognized in SLE pathogenesis. The unique properties of IgD, such as the positively charged amino acids in its long hinge region and its high degrees of somatic hypermutation, may enable IgD to bind many SLE-associated antigens, such as negatively charged double-stranded DNA. These features highlight the strong pathogenic potential of IgD in SLE. We recently discovered that a discrete subset of B cells undergoes a non-canonical form of IgM-to-IgD class switching upon exposure to a specific cocktail of cytokines, including interleukin-21 (IL-21). We also found that IgD binds to myeloid cells such as basophils, mast cells, monocytes and neutrophils, and induces potent inflammatory responses from these cells, including IL-1 and IL-18 production. The present project aims at elucidating the mechanism of dysregulated IgD production in SLE and the function of IgD in SLE-associated inflammation. We hypothesize that elevated IgD production in SLE originates from a pathological imbalance between IgD-inducing and IgD-restraining signals in B cells, including autoreactive B cells. We contend that such imbalance leads to an increased production of IgD antibodies highly reactive to self-antigens, including autologous double-stranded DNA. We argue that this process enhances inflammation by activating interleukin-1 and interleukin-18-processing signaling platforms in myeloid cells.'

Introduzione (Teaser)

A European study is working to address gaps in knowledge of the role of immunoglobulin D (IgD) in autoimmunity onset. Literature reviews emphasise the importance of IgD autoantibodies and deregulated IgD-producing B cells in the development of inflammation-associated autoimmunity.

Descrizione progetto (Article)

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that affects nearly all organ systems, with patients presenting a wide range of symptoms. SLE is associated with an increased production of IgD, an evolutionarily perpetuated immunoglobulin class with no apparent function in health and disease.

Clinical research studies in SLE patients showed deregulated expression and release of certain cytokines (BAFF, CD40L, IL-2, IL-21 and IL-15) elicited IgD class switching. In addition, insufficiency of Vitamin D3 (VD3), a critical immunoregulator of IgD production was seen.

The EU-funded 'Regulation and function of IgD in systemic lupus erythematosus' (ACIGDSLE) project aims at elucidating the mechanism of dysregulated IgD production in SLE and the function of IgD in SLE-associated inflammation. To this end, researchers have decided to investigate the regulation of IgD class switch recombination (CSR) and production by VD3. CSR leads to the loss of surface IgM expression on B cells that further differentiate and secrete IgD.

Hyper-IgD syndrome (HIDS - autoinflammatory disorder) is associated with increased IgD production and inflammation. HIDS occurs due to mutations in the mevalonate kinase (MvK), an enzyme required for cholesterol and VD3 synthesis. Based on this, the running hypothesis of the ACIGDSLE study is that the elevated IgD levels encountered in SLE patients could also stem from deregulation in VD3 synthesis.

To prove this, project members have stimulated purified peripheral blood B cells positive for IgM and IgD with IgD-inducing cytokine cocktails. Preliminary results show that VD3 negatively regulates IgD CSR. IgD-positive B cells are only present in HIDS patients and not in healthy individuals. These findings indicate that HIDS is associated with a deregulated trafficking of IgD class-switched B cells.

The ACIGDSLE study demonstrated that in diseases like SLE, elevated IgD antibody levels are highly reactive towards self-antigens and could worsenI inflammatory process. On a clinical level, this information could be utilised to improve the treatment of SLE and HIDS.