Tregs and Autoimmune Diseases

Figure 1. Schematic representation of the host immune response against microbial pathogens (Source: 18). 

Allergy and hypersensitivity reactions in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance.

Hypersensitivity reactions are immune mediated responses that occur in pre-sensitized hosts.^[41] 

These reactions can be classified into four categories: 

1. Type I, anaphylactic, mediated by IgE; 
2. Type II, cytotoxic, mediated by antibodies recognizing self-antigens; 
3. Type III, immune complex, caused by deposition of antigen-antibody complexes in tissues, leading to the tissue-damaging effects of complement and leukocytes (e.g. Arthus type reaction); and 
4. Type IV, delayed-type hypersensitivity, which is not mediated by antibodies but by T cells.

Naive CD4 T helper cells differentiate into different CD4 T effector lineages after antigen encounter, including Th1, Th2, Th17, Tfh and Treg cells (see Figure 1).

It's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the Th model (i.e., Th1, Th2).  

CD4 T Cells	Key Transcription Factor	Signature  Cytokines	Effects of Overactivation against Antigen
Th1	T-bet STAT4	Triggered by the polarizing cytokine IL-12 and their effector cytokines are IFN-γ and IL-2	Type IV hypersensitivity which include Type 1 diabetes
Th2	GATA3 STAT6	Triggered by the polarizing cytokines IL-4 and IL-2, and their effector cytokines are IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25	Type I hypersensitivity which is an allergic reaction mediated by IgE Are associated with autoimmune disease such as: • allergic rhinitis • atopic dermatitis • asthma
Th17	Stat3 RORγ RORα	Triggered by the polarizing cytokines TGF-β, IL-6, IL-21 and IL-23[31]	Type 3 immune complex and complement-mediated hypersensitivity. Are associated with autoimmune disease such as: • multiple sclerosis[45] • rheumatoid arthritis • psoriasis
Tfh	Bcl-6	Triggered by CD278 or ICOS and their effector cytokines are IL-21 and IL-4	Are associated with antibody-mediated autoimmune diseases, which include SLE and Sjögren syndrome

       Table 1.  Helper T Cells and associated hypersensitivity

Key Transcription Factor

Transcription factors are proteins that help turn specific genes "on" or "off" by binding to nearby DNA. Transcription factors that are activators boost a gene's transcription. Groups of transcription factor binding sites called enhancers and silencers can turn a gene on/off in specific parts of the body.

Lineage-Specific Transcription Factors

When the environment is rich in interleukin (IL)-12 and/or interferon (IFN)-γ, naive CD4 T cells differentiate into IFN-γ-producing Th1 cells, driven by the transcription factor T-bet.

Similarly, IL-4 induces IL-4-producing Th2 cells mediated by the transcription factor GATA binding protein 3 (GATA3).

Traditional Concept—Master Transcription Factor and Signature Cytokines

The traditional concept of CD4 T cell differentiation is that each CD4 T lineage has its own master transcription factor and signature cytokines, such as T-bet for IFN-γ-producing Th1, GATA3 for IL-4-producing Th2 and RORγt for IL-17-producing Th17 cells. However, recent studies have challenged this concept:^[35,36] 

Several lineage specific transcription factors are expressed in more than one lineage: 

For example, T-bet is the master transcription factor for Th1 differentiation and IFN-γ production in Th1 cells, but it is also expressed in encephalitogenic Th17 cells and contributes to the encephalitogenicity of Th17 cells. Similarly, Bcl-6, the key transcription factor for T follicular helper cells (Tfh), is also expressed in early-stage Th1 cells, although the detailed function in Th1 cells have not been well characterized. These data suggest that lineage-defining transcription factors have functions beyond driving lineage-specific cytokine production.

	Foreign	Autoimmune
Type I/allergy/atopy (IgE)	Atopic eczema, Allergic urticaria, Allergic rhinitis (Hay fever), Allergic asthma, Anaphylaxis, Food allergy Common allergies include: Milk, Egg, Peanut, Tree nut, Seafood, Soy, Wheat, Penicillin allergy	Eosinophilic esophagitis
Type II/ADCC IgM IgG	Hemolytic disease of the newborn	Cytotoxic Autoimmune hemolytic anemia, Immune thrombocytopenic purpura, Bullous pemphigoid, Pemphigus vulgaris, Rheumatic fever, Goodpasture syndrome, Guillain–Barré syndrome "Type V"/receptor Graves' disease, Myasthenia gravis, Pernicious anemia
Type III (Immune complex)	Henoch–Schönlein purpura, Hypersensitivity vasculitis, Reactive arthritis, Farmer's lung, Post-streptococcal glomerulonephritis, Serum sickness, Arthus reaction	Systemic lupus erythematosus, Subacute bacterial endocarditis, Rheumatoid arthritis
Type IV/cell-mediated (T cells)	Allergic contact dermatitis, Mantoux test	Diabetes mellitus type 1, Hashimoto's thyroiditis, Multiple sclerosis, Coeliac disease, Giant-cell arteritis, Postorgasmic illness syndrome, Reactive arthritis
Unknown/ multiple	Hypersensitivity pneumonitis, Allergic bronchopulmonary aspergillosis, Transplant rejection,  Latex allergy (I+IV)	Sjögren syndrome, Autoimmune hepatitis, Autoimmune polyendocrine syndrome, APS1, APS2 Autoimmune adrenalitis, Systemic autoimmune disease

Table 2.  Source: [39]

Tregs

The regulatory T cells (Tregs) are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. 

Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.^[36] 

Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells.^[37] Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. 

Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.^[9]

Tregs and Autoimmune Diseases

The autoimmune diseases are attributable to loss of immune tolerance within the patients’ immune systems, which leads to the patients’ own immune cells overreacting or incorrectly attacking ‘self’ antigens in vital organs. 

Tregs expressing the transcription factor FoxP3 (FOXP3⁺ Tregs) are essential to maintain immunologic homeostasis, self-tolerance, and to prevent runaway immune responses.^[23] 

Upregulation and/or maintenance of regulatory T cells (Tregs) during autoimmune insults may have therapeutic efficacy in autoimmune diseases.

The main trend in current therapies is to rely heavily on nonspecific immunosuppressive drugs such as steroids. 

However, these drugs relieve only some of the symptoms, and often have serious side effects particularly if they are used for the long term, due to their indiscriminate immunosuppressive function.

Type I Hypersensitivity

Usually, Treg cells, TR1, and Th3 cells at mucosal surfaces suppress Th2, mast cells, and eosinophils, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in asthma and atopic dermatitis.^[32]

Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis.^[33] Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.^[34]

Type II Hypersensitivity

Type II hypersensitivity reaction refers to an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens with the resultant cellular destruction, functional loss, or damage to tissues.

For the treatment/management of Type II hypersensitivity, read [40] for more details.

Type III Hypersensitivity

In type III hypersensitivity reaction, an abnormal immune response is mediated by the formation of antigen-antibody aggregates called "immune complexes." They can precipitate in various tissues such as skin, joints, vessels, or glomeruli, and trigger the classical complement pathway. Complement activation leads to the recruitment of inflammatory cells (monocytes and neutrophils) that release lysosomal enzymes and free radicals at the site of immune complexes, causing tissue damage.

The principle feature that separates type III reactions from other hypersensitivity reactions is that in type III reaction, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues.

For the treatment/management of Type III hypersensitivity, read [42] for more details.

Type IV Hypersensitivity

Type four hypersensitivity reaction is a cell-mediated reaction that can occur in response to contact with certain allergens resulting in what is called contact dermatitis or in response to some diagnostic procedures as in the tuberculin skin test. Certain allergens must be avoided to treat this condition.

For the treatment/management of Type IV hypersensitivity, read [43] for more details.

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