Cellular Basis Flashcards
Since the DNA rearrangement takes place in a relatively random manner, the specificity of antigen is not limited to pathogenic agents. The reactivity of T and B cells can be targeted toward self-antigens and/or harmless environmental antigens/food/commensal bacterium. To avoid self-reactivity, the immune system has multiple mechanisms to achieve immunological tolerance against self- and non-self antigens (meaning no-reactivity against specific antigens). What will impaired regulation of the immune system result in?
Impaired regulation of the immune responses results in autoimmune- or autoinflammatory-disorders either in a tissue specific or systemic manner (examples in table). We will go over the mechanism that underlies the immune regulation.
For the following autoimmune diseases describe the specificity of the pathogenic T cells.
- Type I (insulin-dependent) diabetes mellitus
- Rheumatoid arthritis
- Multiple sclerosis
- Inflammatory bowel disease
- Peripheral neuritis
- Autoimmune myocarditis
Type I (insulin-dependent) diabetes mellitus- islet cell antigens
Rheumatoid arthritis- unknown antigen in joint synovium
Multiple sclerosis- myelin basic protein, proteolipid protein
Inflammatory bowel disease- unknown
Peripheral neuritis- P2 protein of peripheral nerve myelin
Autoimmune myocarditis- myocardial proteins
What is immunological tolerance? Give a few examples.
non-responsiveness to specific antigens
antigens from the self-tissues, non-self antigens: foods, commensal bacterium, pregnancy.
Tolerance against antigens we are exposed to commonly (food, commensal bacterium) is important to maintain homeostasis of the immune system and prevent autoimmune disorders such as IBD or hyper-immune disorders (allergy)
How does chronic infection or anti-tumor immunity relate to immunological tolerance?
The development of tolerance to pathogen antigens can be catastrophic for the host, not being able to mount effective responses.
Chronic infection often accompanied by immunological tolerance against the infectious agents, leading to recurring infections.
Anti-tumor immunity is often impaired by immunological tolerance provoked by the tumor environment.
Describe the role of T cells.
What are they essential for?
Which T cells are required for tolerance against self-antigens?
T cells are the key regulator (and effectors) of the adaptive
immune responses.
They are essential for induction of antibody production for many antigens (T-dependent antigens), cell mediated pro-inflammatory responses, graft rejection, and cytotoxic response against intracellular pathogens.
A subset of T cells (called regulatory T cells) are required for tolerance against self-antigens. (foxp3+)
Slide 8
What are the two mechanisms of immune tolerance?
Describe/define both.
Regulatory T cells, Myeloid Derived Suppressor cells, Inappropriate stimulation…
central and peripheral
Central tolerance: This is based on elimination of T cells that are reactive to antigens present in the thymus—self antigens.
Peripheral tolerance:
Regulatory T cells—professional T cells that are designed to impose suppression to other immune cells.
Myeloid Derived Suppressor cells (MDSCs): A group of myeloid cells become potent immunoregulatory cells when exposed to inflammatory cytokines (e.g.IFN-γ) and blocks T cell responses. Often tumor associated.
Clonal anergy: When T cells are stimulated in a manner that are not “complete, cells become non-responsive to further stimulation.
What is anergy?
When T cells are stimulated in a manner that are not “complete, cells become non-responsive to further stimulation.
A. Anergy refers to the state of T cells that are unresponsive to antigen stimulation.
B. When naive T cells are presented antigens in the absence of the crucial “second signal (stimulation from CD28), cells get partially activated and undergoes the process that is dominated by degradation of signaling molecules required for activation and becomes non-responsive to further stimulation.
C. Ligand (CD80, CD86) for CD28 is expressed by a limited group of antigen presenting cells. Therefore, when antigen is presented by other type of cells (e.g. tumor cells), cells become anergic in vivo.
Describe clonal selection of self-reactive cells.
Intrathymic clonal deletion during the maturation process of thymocytes eliminate cells that have high affinity to antigens present in the thymus.
Slide 11
Describe AIRE gene. What does it do?
AIRE is a transcription factor that is expressed mainly in the medulla of the thymus. AIRE induces expression of a wide range of genes expressed by other organs (e.g. endocrine gland). This leads to negative selection of thymocytes reactive to these self antigens.
AIRE gene enables thymic stromal cells to express non-thymic genes (e.g. pancreas specific genes) and present self antigens to developing thymocytes.
What will loss of function of AIRE gene lead to?
Loss of functions of AIRE gene leads to severe auto-recessive genetic autoimmune disorder:
Autoimmune polyendocrine syndrome (APS). Endocrine organs are destructed by antibodies and lymphocytes.
Failure of Central tolerance:
Loss of functions of AIRE gene leads to severe auto-recessive genetic autoimmune disorder: Autoimmune polyendocrine syndrome (APS). Endocrine organs are destructed by antibodies and lymphocytes.
What are Hassall’s corpuscles?
Hassall’s corpuscles—is now defined as the site for generation of regulatory T cells. Cells that have intermediate affinity to self-antigens and not eliminated by negative selection
mature into Foxp3+ Tregs.
A group of thymocytes that have reactivity against self-antigens are converted into nTregs. This takes place in the structure called Hassall’s corpuscles.
Hassall’s corpuscles are groups of epithelial cells within the thymic medulla. Human Hassall’s corpuscles express thymic stromal lymphopoietin (TSLP) and help differentiation of FOXP3+ regulatory T cells via activation of a subset of dendritic cells.
Describe the suppression by innate cells.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that are defined by their myeloid origin and ability to potently suppress T cell responses.
They were initially recognized as cells that infiltrate solid tumors and have potent immune-suppressive functions. They suppress in part by response to pre-existing inflammations and activated by cytokines such as IFN-γ. Then in turn produce immuno-inhibitory factors
Describe the following types of T cell mediated tolerance.
Dominant suppression
Cell intrinsic activation.
- Dominant suppression: imposed by professional regulators
- Cell intrinsic inactivation: change of the state of T cells (become unresponsive to antigen stimulation)
Slide 16
Describe nTregs.
What is their role?
Where are they generated?
What do they express? What do mature nTregs also express?
thymus derived Foxp3+ cells. Mainly against self-antigens.
Enforcement by nTregs:
“professional” T regulators, aka “nTregs”. These are cells generated in the thymus and impose suppression of other immune cells, mainly T cells.
Since they are generated in the thymus due to relative high affinity against antigens present in the thymus, their antigen diversity is limited mostly to “self-antigens”.
They express a transcription factor called Foxp3. Foxp3 is essential for generation and/or maintenance of Tregs survival and functions. Mature nTregs also express CD25, IL-2R alpha chain. IL-2 is an essential factor for the maintenance of nTregs.
Describe iTregs.
How can they be influenced?
Which cytokines play critical roles in this case?
Which cytokine is inhibitory for induction of iTregs?
What factors can induce iTregs?
- These Tregs can be manipulated by the environment (food), commensal organisms, pathogens and tumors
- Like many other immune reactions, the cytokine milieu drives the differentiation of a naive T cell in the presence of its antigen. In this case, the presence of dominance of TGF-beta and IL-2 plays critical roles.
Presence of inflammatory cytokines such as IL-6 is inhibitory for induction of iTregs. iTregs are induced by antigen presenting cells that are present in the mucosal environment such as intestine.
Vitamin A and/or D functions as a co-factor to induce iTregs.
