Autoimmune diseases occur in ~5% of people and are caused by immune dysregulation from breakdowns in immune tolerance. A complex array of immune checkpoints is involved in the maintenance of immune homeostasis and, when mutated, can result in autoimmune syndromes (Table 1 and Table 2). Central tolerance for deletion of autoreactive T cells or modification of their TCRs occurs in the thymus, and for B cells with self-reactive B-cell receptors, central deletion occurs in bone marrow. Peripheral tolerance occurs in lymph nodes, spleen, and tissue associated lymphoid tissue such as gastrointestinal tract Peyer’s patches. The sites and modes of peripheral tolerance are varied and reflect the complex cellular and cytokine interactions that occur in mediation of T- and B-cell adaptive immunity. While B- and T-cell deletion by immune cell apoptosis can occur in the periphery, peripheral tolerance can also occur with cell inactivation termed anergy, a state of immune unresponsiveness following contact with antigen. T- and B-cell responses are also dampened in the periphery by Tregs producing TGF-β and IL-10. The result of immune dysregulation in autoimmune disease is the production of a myriad of antibodies against self-antigens (autoantibodies), many of which are pathogenic for the clinical manifestations of the autoimmune disease (Table 3).

Table1. Monogenetic Mutations That Lead to Immune Dysregulation and Autoimmunity

Table2. Immune Tolerance Checkpoints in T- and B-Cell Immunity

Table3. Recombinant or Purified Autoantigens Recognized by Autoantibodies Associated with Human Autoimmune Disorders

Table3. Recombinant or Purified Autoantigens Recognized by Autoantibodies Associated with Human Autoimmune Disorders (Continued)

Tregs are CD4 or CD8 T cells that downmodulate B- and T-cell responses in peripheral lymphoid tissues to prevent autoimmune dis eases, and the transcriptional regulator FOXP3 is centrally involved in the establishment of the Treg phenotype. Mutations in genes that lead to loss of Tregs or their function result in autoimmune and inflammatory syndromes (Table 1). Mutations in FOXP3 lead to an X-linked syndrome characterized by immune dysregulation, polyendocrinopathy, and enteropathy (IPEX). Similarly, mutations in the CD25 (IL-2 receptor α) molecule expressed on Tregs lead to enteropathy, dermatitis, other manifestations of autoimmunity, and susceptibility to infections. Mutations in the checkpoint inhibitor T-cell molecule CTLA-4—also expressed on Tregs—lead to loss of Treg function and result in multiple autoimmune syndromes in humans depending on the CTLA-4 mutation. In mice, knockout of the ctla4 gene leads to massive uncontrolled lymphoproliferation and early death. Finally, mutations in the lipopolysaccharide (lipopolysaccharide-responsive and beige-like anchor [LRBA]) protein cause a syndrome in infants characterized by enteritis, hypogammaglobulinemia, and autoimmune cytopenias.

Chronic viral infections can perturb Treg number and function. In HIV-1 infection, chronic antigenic stimulation leads to shifts in the B-cell repertoire toward an autoimmune permissive state, with increased numbers of autoreactive B cells and decreased CD4+ Tregs leading to serum autoantibodies or clinical manifestations of autoimmune disease in ~50% of untreated HIV-1-infected individuals.

In addition to checkpoint inhibition for cancer immunotherapy, monoclonal antibodies can be used for immune modulation to correct dysregulated immunity in autoimmune diseases to restore normal levels of immunoregulatory tolerance control. Monoclonal therapies have been developed and successfully used for the treatment of autoimmune and inflammatory diseases (Table 4). Some of the monoclonal antibodies such as anti-CD20 (rituximab) have also been used for the treatment of B-cell malignancies. CTLA 4-Fc has been developed to prevent CD28-induced T-cell activation, resulting in immune suppression for rheumatoid arthritis (RA) and transplantation. TNF-α has been shown to play a central role in RA pathogenesis, and anti-TNF-α antibodies have been successful in treatment of RA and are approved for other autoimmune syndromes including other forms of arthritis, inflammatory bowel disease, and psoriasis. Antibodies against α4 integrin block the migration of α4β7+ T cells to the gastrointestinal tract and are used to treat inflammatory bowel disease (IBD). The TH 17 cytokine IL-17 has been found to be overproduced in psoriasis, and monoclonal anti IL-17 antibody therapy for psoriasis is now approved by the FDA.

Table4. Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in Malignancies ^a (Continued)

Table4. Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in Malignancies ^a (Continued)

Table4. Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in Malignancies ^a (Continued)

Tregs are therapeutic candidates for restoring immune tolerance in autoimmune and autoinflammatory diseases, with the prospect of reducing or replacing immunosuppressive drugs. Like CAR T cells, Treg therapy involves expanding autologous Treg cells in vitro and reinfusing them into individuals with autoimmune or inflammatory diseases. To make Treg therapy more targeted for suppression of antigen-specific immune responses, CAR T technology is being used to redirect Tregs to pathogenic T and B cells. Treg cellular therapy is in human clinical trials for the treatment of graft-versus-host disease in the setting of transplantation and for prevention of progression of type 1 diabetes mellitus.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الدينية يطلق الدورة التطويرية والفقهية الخامسة لملاكات العتبة العباسية المقدسة

قسم الشؤون الفكرية ينظّم ختمة قرآنية رمضانية لطلبة العلوم الدينية الأفارقة في النجف

شعبة الخطابة تقيم مجلسا للوعظ والإرشاد في الصحن الشريف تزامناً مع حلول شهر رمضان المبارك

قسم التطوير يختتم دورة إعداد المدربين لملاكات مديرية تربية كربلاء

المزيد

الآخبار الصحية

مفاجأة.. تحسين القدرة على التحمل لا يعتمد العضلات فقط

المرتفعات والأكسجين.. دراسة "مبشرة" لمرضى السكري

علماء يبتكرون "آلية" تتوقع موعد ظهور أعراض الزهايمر

ماذا يحدث لجسمك عند التوقف عن تناول الخضراوات والفواكه؟

المزيد

الآخبار التكنلوجية

رصد "القرش النائم" في أحد أقسى الأماكن على وجه الأرض

أسماك أعماق البحر تكشف نظاما بصريا يتجاوز "المألوف"

زوكربيرغ أمام القضاء في قضية إدمان المراهقين

"علي بابا" تكشف عن نموذج جديد للذكاء الاصطناعي

المزيد

مواضيع ذات صلة

Allergic Rhinitis

Chimeric Antigen Receptor T Cells

Checkpoint Inhibition Therapy for Cancer

Mechanisms of Regulation of T-Cell Activation

Neutrophils & Eosinophils Employ Nets to Entrap Parasites

Immunotherapy

Immune Tolerance and Autoimmunity

Cellular interactions in regulation of normal immune responses

Markers of Granulocytic Maturation

The Complement System Also Protects Against Infection

Monocytopoiesis

Eosinophil Production