 |
| 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:
- Type I, anaphylactic, mediated by IgE;
- Type II, cytotoxic, mediated by antibodies recognizing self-antigens;
- 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
- 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.
References
- Profound Treg perturbations correlate with COVID-19 severity
- Regulatory T-cell therapy shows promise for COVID-19-related respiratory distress
- All About Regulatory T cells (Tregs) & How to Increase Them
- Itch expression by Treg cells controls Th2 inflammatory responses
- Are You Th1 or Th2 Dominant? Effects + Immune Response
- Immunity against Helminths: Interactions with the Host and the Intercurrent Infections
- Endurance Exercise Diverts the Balance between Th17 Cells and Regulatory T Cells
- Influence of Dietary Components on Regulatory T Cells
- Chen W (August 2011). "Tregs in immunotherapy: opportunities and challenges". Immunotherapy. 3 (8): 911–4.
- Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (May 2006). "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells". Nature. 441 (7090): 235–8.
- Vignali, D.A., Collison, L.W., and Workman, C.J. (2008). How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532.
- Panduro, M., Benoist, C., and Mathis, D. (2016). Tissue Tregs. Annu. Rev Immunol. 34, 609–633.
- De Simone, M., Arrigoni, A., Rossetti, G., Gruarin, P., Ranzani, V., Politano, C., Bonnal, R.J.P., Provasi, E., Sarnicola, M.L., Panzeri, I. et al. (2016). Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 45, 1135–1147.
- Plitas, G., Konopacki, C., Wu, K., Bos, P.D., Morrow, M., Putintseva, E.V., Chudakov, D.M., and Rudensky, A.Y. (2016). Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity. 45, 1122–1134.
- Magnuson, A.M., Kiner, E., Ergun, A., Park, J.S., Asinovski, N., Ortiz-Lopez, A., Kilcoyne, A., Paoluzzi-Tomada, E., Weissleder, R., Mathis, D. et al. (2018). Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. Proc Natl Acad Sci U S A. 115, E10672–E10681.
- Lund, J.M., Hsing, L., Pham, T.T., and Rudensky, A.Y. (2008). Coordination of early protective immunity to viral infection by regulatory T cells. Science. 320, 1220–1224.
- Almanan, M., Raynor, J., Sholl, A., Wang, M., Chougnet, C., Cardin, R.D., and Hildeman, D.A. (2017). Tissue-specific control of latent CMV reactivation by regulatory T cells. PLoS Pathog. 13, e1006507.
- Belkaid, C. A. Piccirillo, S. Mendez, E. M. Shevach, D. L. Sacks, Nature 420, 502 (2002).
- Y. Belkaid, B. T. Rouse, Nat. Immunol. 6, 353 (2005).
- B. T. Rouse, P. P. Sarangi, S. Suvas, Immunol. Rev. 212, 272 (2006).
- G. Peng et al., Science 309, 1380 (2005).
- C. Pasare, R. Medzhitov, Science 299, 1033 (2003).
- Josefowicz, S.Z., Lu, L.F., and Rudensky, A.Y. (2012). Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564.
- Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2–P2X7 pathway
- Role of CD4+ CD25+ regulatory T cells in melatonin-mediated inhibition of murine gastric cancer cell growth in vivo and in vitro
- A comparison of low-dose cyclophosphamide treatment with artemisinin treatment in reducing the number of regulatory T cells in murine breast cancer model
- Metabolic regulation of regulatory T cell development and function
- Regulatory T cells Facilitate Cutaneous Wound Healing
- Bodnar RJ. Epidermal Growth Factor and Epidermal Growth Factor Receptor: The Yin and Yang in the Treatment of Cutaneous Wounds and Cancer. Adv Wound Care. 2013;2:24–29.
- Immune- and non-immune-mediated roles of regulatory T-cells during wound healing
- Th17 cytokines in mucosal immunity and inflammation
- Soyer, OU; Akdis M; Ring J; Behrendt H; Crameri R; Lauener R; Akdis CA (2012). "Mechanisms of peripheral tolerance to allergens". Allergy. 68 (2): 161–170.
- Petalas, K; Durham SR (2013). "Allergen immunotherapy for allergic rhinitis". Rhinology. 51 (2): 99–110.
- Cernadas, JR (Feb 2013). "Desensitization to antibiotics in children". Pediatr Allergy Immunol. 24 (1): 3–9.
- Oestreich KJ, Weinmann AS. Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors. Nat Rev Immunol. 2012;12:799–804.
- Impact of suppressing retinoic acid-related orphan receptor gamma t (ROR)γt in ameliorating central nervous system autoimmunity
- Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (May 2006). "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells". Nature. 441 (7090): 235–8.
- Curiel TJ (May 2007). "Tregs and rethinking cancer immunotherapy". The Journal of Clinical Investigation. 117 (5): 1167–74.
- Type II hypersensitivity (Wikipedia)
- Type II Hypersensitivity Reaction
- Committee IoMUVS. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington,(DC: National Academies Press (US), 1994.
- Type III Hypersensitivity Reaction
- Type IV Hypersensitivity Reaction
- Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation
- Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System (good)
- Upregulation of serum IL-23 strengthens the case for Th17 activity
- Ulusoy C, Tuzun E, Kurtuncu M, Turkoglu R, Akman-Demir G, Eraksoy M. Comparison of the cytokine profiles of patients with neuronal-antibody-associated central nervous system disorders. Int J Neurosci (2012) 122(6):284–9.
- Dendritic Cells—Messengers between Innate and Adaptive Immune Systems
- Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms
