Tolerance & Autoimmunity Overview

Tolerance & Autoimmunity

• Tolerance is a state of immune non-responsiveness to self.
• Autoimmunity reflects a loss of tolerance, involving autoreactive B and T cells.
• Tolerance is generated by two main mechanisms: central tolerance and peripheral tolerance.

Aims of Sessions

• Promote awareness of: developmental aspects of autoimmunity, induction and loss of central tolerance, thymic selection, peripheral tolerance mechanisms, and an overview of autoimmune disease.

Cross Section of the Thymus

• The thymus is a crucial organ in immune development.
• Images show the main parts of the thymus (capsule, cortex, medulla, interlobular septum and thymic lobule).
• Inside the thymus are "thymic corpuscles".

Migratory Route of Developing T Cell

• T cells develop in different stages, migrating from the subcapsular region through the cortex and into the medulla of the thymus.
• Immature thymocytes progress through different stages (DN1, DN2, DN3, DN4) and then double-positive and mature.
• T cells are released into circulation after maturation.
• Different cell types are shown at each stage (macrophage, dendritic cell and epithelial cell).

T Cell Developmental Outcome

• Positive selection of T cells occurs when T-cell receptors (TCRs) with moderate binding to major histocompatibility complex (MHC) molecules are retained.
• T cells that bind too weakly are eliminated (neglect).
• Cells that bind too strongly are eliminated (clonal deletion).
• Some T cells that bind strongly to MHC develop into regulatory T cells.

+ve & -ve Selection in a Nutshell

• Positive selection in the thymus cortex involves selecting T cells that react to self-MHC, in a moderate range.
• T cells with weak binding to MHC die (in the cortex).
• Negative selection in the thymus medulla involves selecting T cells that intensely bind self-antigen, and these are also eliminated.

Autoimmune Regulator (AIRE) Gene

• AIRE modulates the transcription of peripheral self-antigens displayed in the thymus.
• This allows maturing T cells to learn about and tolerate a wide range of self-antigens.
• Immature thymocytes with a high affinity for self-antigens undergo apoptosis.

Central Tolerance in T Cells

• Central tolerance does not delete T cells that are autoreactive to organ-sequestered antigens and cryptic epitopes.
• A subset of these T cells are potentially pathogenic:
• Deletion
• maintenance of immunologic ignorance
• functional inactivation (anergy)
• suppression

A Quick Reminder

• Two signals are needed for full T-cell activation: specific signal and co-stimulatory signal.
• Specific signal alone leads to anergy (failure to activate).
• Co-stimulatory signal alone has no effect on T cells.

Peripheral T Cell Tolerance Overview

• Mature T cells that recognize self-antigens in peripheral tissues are rendered unresponsive.
• Mechanisms of action include anergy (unresponsiveness), engagement of inhibitory receptors (like CTLA-4), and suppression by regulatory T cells.

Suppression via Regulatory T Cells

• Regulatory T cells suppress autoreactive T cells by interacting with antigen-presenting cells (APCs).
• Deletion and non-co-stimulation are also methods of activation induced death.

Inhibitory Receptors (Cytotoxic T Lymphocyte Antigen-4)

• CTLA-4 is an inhibitory receptor on CD4+ T cells that binds B7 proteins on APCs.
• It hinders activation and proliferation of T cells.
• CTLA-4 binds B7 with greater affinity than CD28.

Programmed Death-1

• PD-1 has two ligands, PD-L1 and PD-L2.
• PD-1 impacts both central and peripheral tolerance.
• May work with CTLA-4 to regulate T cell activation and cytokine production.
• A possible mechanism of tumour immune evasion is the expression of PD-L1/2.

Important Points to Note

• Persistence, Location and characteristics of APCs, and presence of adjuvants may influence tolerance over an immune response to protein antigens.

Regulatory T Cells

• Regulatory T cells are a subset of CD4+ T cells that express IL-2 receptor α chain (CD25) and Foxp3, a forkhead transcription factor.
• High levels of CTLA-4 are also expressed.
• Two types are known (natural-thymus and adaptive-induced).

Maintenance & Mechanisms of Action of T Regs

• Regulatory T cell function relies on TGF-β and IL-2.
• TGF-β encourages Foxp3 presence.
• IL-2 promotes regulatory T cell differentiation.
• IL-2 activates STAT5.
• T cell activation can be suppressed in lymphoid organs and tissues, in the effector phase, through multiple mechanisms.

How Are Regulatory T Cells Generated?

• TCR signal strength influences T-cell development: strong signals lead to regulatory T cell (Treg) formation; weak signals give rise to conventional T cells.
• Deletion of T cells and production of Tregs are influenced by factors like IL-2, and the strength of TCR signaling.

Recap 1

• Many lymphocytes have some degree of self-reactivity and can respond to foreign antigens.
• If all self-reactive lymphocytes are removed, the immune system is impaired.
• Autoreactivity happens because self-recognition is less exact.

Recap 2

• A high percentage of thymocytes (98%) undergo apoptosis in the thymus due to intensive screening.
• Thymocytes are tested for their ability to recognize self-peptide within self-MHC complexes This is key for self-tolerance.
• Self-antigens manifest in different forms: cell surface antigens, intracellular antigens and soluble antigens.

Inhibitory Cytokine Release

• Interleukin-10 (IL-10) inhibits the production of IL-12 by activated macrophages and dendritic cells.
• IL-10 hinders co-stimulator and MHC Class II expression.
• IL-10 has broad roles in immune control (e.g., in mucosal tissues).
• Tumour Growth Factor- β (TGFβ) suppresses T-cell proliferation and macrophage activation.

Activation-Induced Cell Death

• Fas/FasL ligation drives activation-induced cell death (AICD).
• Repeated stimulation can trigger cell death in mature T cells, triggered by self-antigens.
• Defects in AICD pathways correlate with autoimmune conditions like lymphoproliferative syndrome.

B Cell Central Tolerance

• Central B cell tolerance occurs in the bone marrow.
• This process is crucial for maintaining unresponsiveness to thymus-independent self-antigens.
• Immature B cells that strongly bind self-antigen go through receptor editing or deletion.
• B cells with weak self-antigen binding become anergic.

B Cell Receptor Editing

• Immature B cells that recognize self-antigens in high concentrations can undergo receptor editing.
• Cross-linking of self-antigens activates RAG1 and RAG2 (recombination-activating genes).
• This process leads to VJ recombination in the Ig κ locus, allowing self-antigen-specific BCRs (B cell receptors) to re-specificity.

Peripheral B Cell Tolerance

• Mature B cells outside the bone marrow can become anergic or die by apoptosis in the absence of specific T helper cells.
• Encountering strong self-antigen crosslinking leads to clonal deletion.
• Continual presence of soluble self-antigen can result in B cell anergy.

PTPN22 Risk Allele

• PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp).
• Lyp is found exclusively in immune cells.
• Location is on chromosome 1p13.3-13.1.
• Reduced B-cell signaling causes defects in central B-cell tolerance, leading to an accumulation of autoreactive B cells.
• Possibly involved in T-cell selection.

Immune Privilege

• Sequestered antigens in certain tissues shield these tissues from immune responses.

How Does Tolerance Break Down?

• Tolerance breakdown may involve numerous mechanisms, with the overcoming of T-cell peripheral tolerance appearing to be a significant hurdle in some circumstances.
• Potential breakdowns include reversal of active tolerance mechanisms or the overcoming of protective processes
• Tolerance breakdowns can happen in infections and tissue damage, and may lead to more specific tissue damage.

Molecular Mimicry

• Molecular mimicry occurs when antibodies that are stimulated by a microbial antigen cross-react with human tissue causing subsequent diseases.

Co-stimulation Requirements Vary with Differentiation of T Cells

• The activation requirements for various T-cell types involving specific signal and co-stimulatory signals are different.
• Two signals are needed for full T-cell activation.

A Concept of Tolerance Breakdown

• Breakdown of tolerance can involve tissue damage, changes in self-antigen presentation, and alterations of co-stimulators and MHC molecules.

Loss of Tolerance

• AIRE protein involvement (self-peptide presentation):
• CTLA-4 expression on activated T cells (binding to B7, inducing anergy)
• Foxp3's importance in Treg cells; its presence relates to autoreactive T-reg cell development.
• The transitioning or shift between regulatory and other T-cell types.
• Fas expression and apoptosis induction

Overview of Autoimmune Disease

• Autoimmune disease affects 5-7% of the developed world's population. Women are more likely to be affected.
• Autoimmune disorders show familial clusters and rising incidence rates.
• Clinically, they are often categorized as systemic or organ-specific.

Autoimmune Disease is Multifactorial

• Genetics and environmental exposures (including infections) are contributors as well as imbalances in immune regulation cause autoimmunity.

Criteria for Definition of an Autoimmune Disease

• Criteria for diagnosis include serum autoantibodies/cell-mediated activity, the presence of both at sites of tissue damage, and the association of levels of autoantibody/T cells with disease activity; and the improvement of the disease following reduction of the autoimmune response.

Additional Criteria for Autoimmune Disease

• Transfer of autoantibodies/T cells can cause the disease in a recipient.
• Immunization with an autoantigen can induce an autoimmune reaction.

Explore the concepts of immune tolerance and autoimmunity through this quiz. Understand the mechanisms behind central and peripheral tolerance, as well as the thymus's role in T cell development. Gain insights into autoimmune diseases and the importance of immune non-responsiveness.