L(3)4 - Cellular Basis of Autoimmunity 2 (mainly about the rest) Flashcards
- to review the function of different leukocytes in organ-specific autoimmunity - to understand how knowledge of the cellular immunology relates to treatment strategies
What are the three signals required for full T cell activation, and what happens when they are not all present?
Signal 1: Recognition of the antigen by the T cell receptor (TCR) on the T cell, presented by an antigen-presenting cell (APC). Alone, this leads to anergy (T cell inactivation).
Signal 2: Co-stimulatory signals provided by the APC through molecules like CD80 or CD86 binding to CD28 on the T cell. Together with Signal 1, this leads to T cell activation.
Signal 3: Cytokines secreted in the microenvironment. This determines the type of immune response and provides further instruction for differentiation into specific T cell subsets (e.g., Th1, Th2).
Without all three signals, activation is incomplete, leading to energy rather than a functional immune response.
Why is co-stimulation important in T cell activation, and what is its implication in tissue culture?
It provides an additional independent pathway necessary for T cell activation. In tissue culture, presenting only the antigen (Signal 1) without co-stimulation (Signal 2) results in T cell anergy rather than activation. This demonstrates the requirement for multiple signals in a complete immune response.
What determines the cytokine environment during T cell activation, and why is this important?
the type of antigen encountered (which can be specific for the location) and the innate immune response. Different antigens elicit specific local cytokine profiles, which guide the differentiation of T cells into subsets (e.g., Th1, Th2, Th17). This is critical for tailoring the immune response to eliminate the pathogen.
What are innate lymphoid cells (ILCs), and how do they contribute to the immune response?
immune cells that lack antigen-specific receptors but play a key role in the early immune response. They produce cytokines and help shape the adaptive immune response by influencing the cytokine environment and recruiting other immune cells. Examples include ILC1, ILC2, and ILC3, which are associated with distinct immune functions.
How does molecular mimicry contribute to autoimmunity?
Molecular mimicry occurs when T cells recognise self-antigens that resemble foreign antigens (e.g., from pathogens). This can lead to the activation of autoreactive T cells, which traffic to target organs and cause local inflammation, recruiting other immune cells and resulting in tissue damage.
What happens during the activation of naive T cells that recognise autoantigens?
Naive T cells recognising autoantigens may become activated through processes like molecular mimicry or bystander activation. They then survey the body and localise to the target organ, where they encounter antigen-presenting cells expressing related antigens. This leads to local inflammation, recruitment of other immune cells (e.g., B cells), and tissue damage.
What immune cell populations are commonly found in inflamed target organs during autoimmunity?
in autoimmunity e.g. experimental autoimmune uveitis (EAU), the following immune cells are commonly found:
CD11b+Ly6G- cells: Monocytes/macrophages (largest proportion).
CD11b+Ly6G+ cells: Neutrophils.
CD4+ T cells.
Other CD45+ cells.
CD8+ T cells.
NK1.1+ cells: Natural killer cells.
What roles do regulatory cytokines like IL-10 and IL-35 play in autoimmunity?
IL-10 (anti inflammatory) and IL-35 (immunosuppressive) help mediate immune regulation and promote tolerance. They contribute to the generation of systemic and local tissue memory, facilitating periods of remission in autoimmune diseases. However, reactivation of autoimmunity can occur under certain conditions.
How can autoimmune processes in the eye (e.g., experimental autoimmune uveitis) be studied?
using induced models in mice e.g.
Taking pictures of the retina to observe damage, such as retinal thinning and colour changes, analysing immune cell populations in the retina to characterise inflammation, Identifying immune cells like CD4+ T cells, monocytes, and neutrophils that accumulate in the inflamed retina.
How do therapeutic opportunities in autoimmunity arise?
through understanding the complex interactions in the immune system e.g. targeting specific cytokines or immune pathways, modulating T cell activation and co-stimulation, addressing local tissue inflammation and repairing tissue damage and research into target organs (e.g., the eye in autoimmune uveitis) provides insights into potential treatments.
What is the significance of CD4+ T cell differentiation in human disease?
Different CD4+ T cell subsets correlate with distinct forms of human diseases. e.g. studies on leprosy revealed that resistance or susceptibility to the disease is associated with specific cytokine production patterns in CD4+ T cells.
How do cytokine patterns differ between resistant and susceptible forms of leprosy?
- Resistant form (tuberculoid leprosy): Cytokines e.g. IL-2, IFN-γ, and IL-10 correlate with strong cell-mediated immunity.
- Susceptible form (lepromatous leprosy): Multibacillary lesions with reduced resistance correlate with distinct cytokine profiles, showing weaker cell-mediated immunity.
How was the correlation between cytokine production and resistance in leprosy studied?
Skin biopsy specimens from leprosy patients were used to extract mRNA, which was amplified by PCR using cytokine-specific primers. This technique identified the cytokine profiles associated with resistant and susceptible forms of the disease.
How do transgenic T cells help study CD4+ T cell phenotypes in autoimmunity?
Transgenic T cells with TCRs that recognise specific autoantigens, e.g. MOG peptide, allow researchers to study the clinical manifestations and severity of autoimmune diseases in relation to T cell differentiation.
what is the MOG peptide
minor compnent of the CNS myelin
How do different CD4+ T cell subsets affect disease severity in autoimmunity?
correlate with varying disease severity e.g.
- Th17 cells: Produce a more severe clinical phenotype.
- Th2 cells: Produce a less severe clinical phenotype.
(highlights the link between T cell differentiation and disease outcomes)
What factors influence the differentiation of CD4+ T cells?
- Genetics plays a key role in determining effector molecules e.g. cytokines / costimulation and susceptibility.
- Costimulatory molecules influence differentiation by modulating the activation signals.
- Environmental factors e.g. how the antigen is administered (route) , its presence, activity (adjuvant), and dose
(4. dendritic cells phenotype)
How do dendritic cells influence CD4+ T cell differentiation?
in promoting the differentiation of specific T cell subsets. By presenting antigens in different contexts, dendritic cells can drive CD4+ T cells towards Th1, Th2, Th17, or regulatory T cell phenotypes.
What are the differentiation cytokines for Th1
IL-12 ( IL-18)
What are the effector cytokines for Th17
IL-6, TGFB1, IL-23 ( IL-21)
What are the effector cytokines for Treg
IL-2 and TGFB1
How is the manifestation of the T cell phenotype determined
by their transcriptio factors e.g. Th1 = Stat4, Th17 = Stat3 and Treg = FoxP3
What kind of T cells are causing organ-specific autoimmune diseases
predominantly Th1 and Th17 cells
When does T cell differentiation occur
after a naive T cell has been activated ( some phenotypes will have a much greater likelihood of causing organ specific autoimmunity and will be found in that specific organ more commonly than others)