**2. Immune dysregulation that leads to SLE**

*Lupus - Need to Know*

abnormalities.

include:

current standard of care [1].

12,600 end-stage kidney disease (ESKD) caused by SLE, are refractory for all

Clinical presentations of SLE, prototype autoimmune disease for interferon activation, are highly heterogeneous, ranging from mild systemic inflammation that affects skin or joints to severe organ damage (brain, kidney, lung etc.). Heterogeneity of clinical presentations requires diverse treatment protocols, addressing multiple immune abnormalities affecting variety of organs. The exact etiology of SLE is not completely understood. Pathogenesis of SLE comprises genetic, environmental, and hormonal factors which induces multiple immune cell lines and systems act abnormally which are mostly explained by autoimmune activation. All etiopathogenic immune pathways targeted with chemotherapy or biologics to date have failed to improve some portion of SLE patients. Heterogeneity of clinical presentations require diverse treatment protocols, addressing immune

There is an urgent clinical need for an effective treatment of chronic autoimmune diseases induced by abnormal activation of immune system that result in multiple organ damage in SLE and in others [1–3]. The current standard of care includes high dose corticosteroids, chemotheraphy with azathioprine, cyclophosphamide, mycophenolate mofetil, cyclosporin, and combination of all with biologics such as rituximab (Anti-CD20) or belimumab (anti-Blsy) [4, 5]. Current modalities that are available to treat SLE and SLE like diseases are immune suppressive and have toxic side effects. After treatments with corticosteroids and chemotherapy, patients become even more vulnerable to pathogens and develop sepsis and septic shock. In many patients, even combinations of all available medications are not effective in controlling the disease progression and development of end stage organ failure. Innovation of nontoxic cellular therapies that target both, the vascular wall and the immune responses within the local microenvironment, are needed. In many patients, even combinations of all available medications are not effective in controlling the disease progression and development of end stage organ failure. Collectively, at least 10–15% of patients fail to respond to all existing treatments. Specifically, three groups of SLE patients with the greatest unmet need

1. 7–8% of patients who have severe nervous system involvement refractory to

2. 10–30% patients with severe nephritis who do not respond to cytotoxic and immune suppressing therapy or available biologic treatment (such as belimumab and rituximab) and become dependent on dialysis leading to death

3. 2–5% of patients develop thrombotic thrombocytopenic purpura who do not respond to combination of cytotoxic medications, immune suppressants, plasma exchange, and biologics, with mortality rate of 34–62% [7].

Disease burden of SLE and lupus nephritis in the US is estimated at 313,436 (100/100,000) and 63,256 (20/100,000), respectively [8–10]. Approximately 10 to 20 percent of patients with lupus nephritis progress to end-stage renal disease as

Unfortunately, there is still no uniformly effective treatment targeting both cellular and humoral autoimmunity for SLE. Therapies targeting components of cellular or humoral immune system fails to induce sustained remission in disease activity in multicenter clinical trials. To design a new treatment that can control the cellular

cytotoxic and immune suppressing medications [6];

they do not respond to commercially available treatments.

within 15 years [1]; and

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Pathogenesis of SLE comprises genetic, environmental, and hormonal factors resulting in multi-system autoimmune inflammatory disease. **Systemic Lupus Erythematosus** [11] is suggested to be the prototype of several systemic inflammatory diseases that are induced by abnormal activation of the type I (−α, −β) [12] and II (−ɣ) interferon (IFN) [13] pathways. Interferon activation results in multiple immune cellular abnormalities, including; dendritic cells (DC), natural killer (NK) cells, cytotoxic T cells, T regulatory cells (Tregs), and autoreactive B cells [14].

SLE is characterized by irregularities in innate cellular and humoral immunity functions [15]. Abnormal T-cells and B-cells recognize self-antigens resulting in immune hyperactivity and autoantibody production that ends up in a multisystem inflammatory disease.

Immune dysregulation in SLE has been described by not one but multiple cell lineages such as CD4+ and CD8+ T-cells, dendritic cells (DC), Natural Killer (NK) cells, B-cell overproduction of autoantibodies, and T regulatory (Treg) cell dysfunction. CD8+ T cells and NK cells have decreased cytotoxic activity. There is a general inability of TGF- β production, which in return accounts for sustained T and B cell hyperactivity and reduced Tregs activity and numbers. There is a disproportional balance between the activated and tolerogenic DCs during SLE activity that limits the expansion of Tregs [16]. The remaining small amount of Tregs that are still existing during the inflammatory activity of lupus are not sufficient to overcome the strong T-cell activation [17, 18].

In both human patients with SLE and in lupus prone mice models, CD4 + CD25 + Foxp3+ Tregs are reported to be decreased during disease activity. CD4+ T helper cell subset (Th17 cells) are increased in SLE in response to IL-17 activation [19, 20]. Blockage of IL-17 has also been suggested as a new treatment option [21, 22].

Restoration of T-cell functions are important for disease control. On the other hand, lupus-like autoimmunity can result simply due to B-cell hyperactivity, with either minimal or no contribution from T-lymphocytes. B cell hyperactivity results with production variety of IgG and IgM autoantibodies directed against nuclear components such as double stranded (ds) DNA and/or single stranded (ss) DNA. Both anti-ssDNA and anti-dsDNA are involved in disease pathogenesis and clinical progress [23, 24].

The type I interferon system appears to play a critical role in SLE etiopathology [11, 25–27]. All the cellular and humoral immune abnormalities seem to activate type I interferons, which in return charge the immune cells further and result in loss of tolerance. Type I interferons control dendritic cell maturation into antigen presenting cells which contribute to B-cell hyperactivity and induce a Th1 response and sustain T-cell activation [28, 29]. Type I interferons are not controlled well and are in excess amount partially due to deficiency of Treg activities in SLE [30–33].

Another major etiopathogenic immune pathway is explained by multiple complement pathway abnormalities. Complement deficiency can be seen up to 5% of all lupus patients [34]. In addition, 50% of SLE patients with deficiencies or dysfunction of the early classical complement pathway develop a lupus-like disease.
