Immunology
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Immunology in Endocrinology
Dr. Jim Johnson, Ph.D. Assistant Professor, Dep t. of C ellular and Physiological Sciences and Dep t. of Surgery, University of British C olumb ia 5358 Life Sciences Building Lab W eb site: www.diab etes.ub c.ca Office: (604) 822-7187 E-mail: [email protected] c.ca
Immunology in Endocrinology Outline and Objectives: 1) 2) 3) 4) 5) 6)
Immunology basics - self versus non-self Immunology basics - specific cell types Immunology basics - T-cell activation Immunology in Endocrinology - Other diseases Immunology in Endocrinology - Type 1 diabetes Immunology in Endocrinology - Type 2 diabetes
Immunology basics - Self versus non-self ‘Immunity’ refers to the global ability of the host to resist the predation of microbes that would otherwise destroy it. Immunity has many facets, but the greatest dichotomy separates adaptive immunity (‘acquired immunity’) from innate immunity (‘natural immunity’ or ‘innate resistance’). A key element of immunity is the recognition of ‘self’ and of ‘nonself’. Errors in this recognition lead to autoimmune diseases, likely type 1 diabetes. A complex array of cell types control this process.
Immunology basics - Innate vs. Adaptive Immunity The immune system is typically divided into two categories--innate and adaptive--although these distinctions are not mutually exclusive. Innate immunity Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body. These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. The innate immune response is activated by chemical properties of the antigen. Adaptive immunity Adaptive immunity refers to antigen-specific immune response. The adaptive immune response is more complex than the innate. The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a "memory" that makes future responses against a specific antigen more efficient
Immunology basics - Cellular vs. Humoral Immunity
Questions or discussion Where are the ‘weak links’ in the immune system?
?
Immunology basics - Specific cell types
Immunology basics - Hematopoietic stem cells
Questions or discussion What is the proof, in the lab or in the clinic, that these cells are truly stem cells?
?
Immune cell types
Immune cell types Red blood cell
Monocyte Neutrophil
Platelet
Immune cell types - B cells B lymphocytes (from Bursa of Fabricius) These cells are major antibody producers. •Plasma B cells are actively producing antibodies. •Memory B cells respond quickly following a second exposure to a specific antigen
Immune cell types - T-cells T-lymphocytes - mature in the thymus These cells are a major mediators of cell-mediated immunity.
T-lymphocytes - T-cell receptor T-lymphocytes talk with antigen-present cells using the T-cell receptor. The signal from the T cell complex is enhanced by simultaneous binding of the MHC molecules by a co-receptor. The co-receptor on helper T cells is CD4, which exclusively binds the class II MHC. The co-receptor on cytotoxic T cells is CD8, which is specific for class I MHC. The co-receptor not only ensures the specificity of the TCR for the correctly-presented antigen but also allows prolonged engagement between the antigen presenting cell and the T cell and recruits essential molecules (e.g., LCK) inside the cell that are involved in the signaling of that activated T lymphocyte.
T-lymphocytes - T-cell activation
T-lymphocytes - T-cell activation signalling pathways
T-cell activation - The role of Ca2+ signals A cytosolic Ca2+ signal is an essential early event in T cell activation.
T-cell activation - The immunological synapse T-cells ‘lock’ onto antigen presenting cells via a ‘synapse’.
T-cell activation - The immunological synapse T-cells ‘lock’ onto antigen presenting cells via a ‘synapse’.
T-cell activation signals proceed the formation of the ‘synapse’.
T-cells - Immunosuppressant drugs block T-cell activation Islet transplant drugs: Tacrolimus (FK506) - blocks calcineurin Sirolimus (rapamycin) - blocks mTOR Daclizumab - antibody against IL-2R
T-cell activation - Shape changing
T-cell activation - signals controlling cytoskeleton reorganization
Questions or discussion Any questions on T-cell activation. What types of signal coding are involved?
?
Immune cell types - Subsets of T-cells Helper T cells - Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Cytotoxic T cells - Destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells. Memory T cells - A subset of antigen-specific T cells that persist after an infection. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+. Regulatory T cells - (a.k.a. suppressor T cells). These are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing fatal autoimmune disease. Natural Killer T cells - bridges the adaptive immune system with the innate immune system. NKT cells recognize glycolipid antigen presented by a molecule called CD1d, rather than MHC. Once activated, these cells initiate both cytokine production and release of cell killing molecules. T cells - possess a distinct TCR on their surface. 5% of all T cells. Autoaggressive T cells - characterized by CD40 expression, which is typically is associated with antigen-presenting cells. Th40 cells are expanded in autoimmune subjects.
Regulatory T cells - Help suppress responses when appropriate This subset of T cells is identified by the expression of CD4, CD25 and FoxP3.
Regulatory T cells - Help suppress responses when appropriate
Mechanism of bystander suppression. Tregs that are activated by DCs in an antigen-specific fashion release IL-10. Once released, IL-10 inhibits immune reactions not only against the initial antigen (dot) but also against other antigens (square, triangle) in a nonspecific fashion.
Questions or discussion Do antigen-specific Tregs have potential therapeutic value?
?
Immune cell types - Natural killer cells Natural killer cells These cytotoxic cells are a major component of the innate immune system. They release granules of perforin and granzyme that cause cells to undergo apoptosis.
Immune cell types - Macrophages Macrophage (greek for big eaters) These cells roam tissues looking for ‘foreign cells’ or dead cells. They also display antigens via MHC class II.
Immune cell types - Neutrophils Neutrophils are granulocytes, filled with neutrally-staining granules which contain enzymes that help the cell to kill and digest microorganisms it has engulfed. The neutrophil has a lifespan of about 3 days.
Non-segmented neutrophils are younger.
Immune cell types - Neutrophil targeting and tissue invasion
Immune cell types - Neutrophils communicate with other cells Through cell–cell contact and secreted products, neutrophils recruit and activate monocytes, dendritic cells (DCs) and lymphocytes, and products of monocytes, macrophages and T cells activate neutrophils. Tissue macrophages ingesting apoptotic neutrophils produce less interleukin23 (IL-23). IL-23 triggers T cells in secondary lymphoid tissues to produce IL-17. IL-17 triggers stromal cells in the bone marrow to produce granulocyte colony-stimulating factor (G-CSF). G-CSF promotes proliferation of neutrophil precursors and release of neutrophils into the circulation (see text for references). BLyS, tumour-necrosis factor-related ligand B-lymphocyte stimulator; CXCL12, CXC-chemokine ligand 12; IFN, interferon-; TNF, tumournecrosis factor.
Neutrophils - Release serine proteases with specific targets
Neutrophils - A movie
Questions or discussion What dangers are there for people who are ‘neutropaenic’? What could cause this?
?
Autoimmune diseases - A partial list •Type 1 diabetes (possibly also type 2 diabetes) •Graves’ diseases •Hashimoto’s diseases •Systemic Lupus Erythematosus (SLE) •Multiple sclerosis •Rheumatoid arthritis
Autoimmune diseases - Graves’ and Hashimoto’s diseases
Graves' disease is a thyroid-specific autoimmune disorder in which the body makes antibodies to the thyroid-stimulating hormone receptor (TSHR), leading to hyperthyroidism, or an abnormally strong release of hormones from the thyroid gland.
Chronic thyroiditis (Hashimoto's disease) is a slowly developing persistent inflammation of the thyroid which frequently leads to hypothyroidism, a decreased function of the thyroid gland. Middle-aged women are most commonly affected.
Autoimmune diseases - Systemic lupus erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic, usually life-long, potentially fatal autoimmune disease characterized by unpredictable exacerbations and remissions with variable clinical manifestations. In Lupus SLE there is a high probability for clinical involvement of the joints, skin, kidney, brain, lung, heart, serosa and gastrointestinal tract. African-Americans and Asians are disproportionately affected. There is a female to male sex bias of 8:1.
Autoimmune diseases - Multiple sclerosis
Multiple sclerosis is a central nervous system disorder marked by decreased nerve function with initial inflammation of the protective myelin nerve covering and eventual scarring. Symptoms and severity of symptoms vary widely and may progress into episodes of crisis alternating with episodes of remission.
Autoimmune diseases - Rheumatoid arthritis
Rheumatoid arthritis is a systemic autoimmune disease which initially attacks the synovium, a connective tissue membrane that lines the cavity between joints and secretes a lubricating fluid.
Questions or discussion What do autoimmune diseases have in common? What does this tell us?
?
Autoimmune diseases - Type 1 diabetes Type 1 diabetes is one of the most common and most expensive autoimmune diseases. Frequent urination Excessive thirst Unexplained weight loss Extreme hunger Sudden vision changes Tingling or numbness in hands or feet Feeling very tired much of the time Very dry skin Sores that are slow to heal More infections than usual Nausea, vomiting, and stomach pains
Type 1 diabetes - Diagnosis
Type 1 diabetes - A model autoimmune disease Type 1 diabetes: 1) is associated with marked infiltration of T-lymphocytes. 2) can be transferred from one mouse to another by auto-reactive T-cells. 3) can be impeded (in mice) by treatments that suppress the immune system Insulin / CD3+ T-cells
Type 1 diabetes - a model autoimmune disease
Type 1 diabetes - Natural history of disease progression
Type 1 diabetes - Genetic susceptibility IDDM 1 - HLA genes
•In humans, the 3.6-Mb (3 600 000 base pairs) MHC region on chromosome 6 contains 140 genes. About half have known immunological functions. •MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. •Thus, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. •The strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes.
Type 1 diabetes - genetic susceptibility IDDM 1 - HLA genes
MHC Class 1
MHC Class 2
Type 1 diabetes - genetic susceptibility IDDM 1 - HLA genes
Type 1 diabetes - genetic susceptibility IDDM 2 - insulin gene The IDDM2 locus contributes about 10% of the type 1 diabetes risk that is synergistic with HLA. The IDDM2 locus contains a sequence of repeated DNA called a variable number tandem repeats (VNTRs). There are three classes of VNTR in the insulin gene: • Class I has alleles that range from 26 to 63 repeat units - common in Caucasians (70% of alleles), confers risk. • Class II has alleles that average around 80 repeat units - rare. • Class III has alleles ranging from 141 to 209 repeat units - protective. The presence of at least one class III allele is associated with a 3-fold reduction in the risk of type 1 diabetes, compared with common I/I homozygote genotype. Because the VNTR occurs in a non-coding region, its influence on diabetes risk cannot be attributed to an alteration of the protein sequence. The VNTR probably affects the transcription of the insulin gene. Class III alleles are associated with 15-30% lower INS mRNA in the pancreas, but higher INS mRNA in the thymus. The thymus helps train the developing immune system by deleting autoreactive T cells. Because the longer VNTRs cause more insulin to be produced in the thymus, the detection and deletion of autoreactive T cells may be more efficient. This improved immune tolerance to insulin would lessen the risk of a future onset of type 1 diabetes caused by anti-insulin antibodies.
Chromosome 11
Questions or discussion Is there an alternative hypothesis for the effects of the insulin VNTR?
?
Type 1 diabetes - Human susceptibility genes IDDM 3-18
Type 1 diabetes - Genetically susceptible NOD mice
NOD mouse
Human
Mouse diabetes genes are denoted with lower case (i.e. iddm1-27).
Type 1 diabetes - Hundreds of cures for NOD mice
Questions or discussion Do any of these work in humans? What does that tell us?
?
Type 1 diabetes - Autoantibodies Most, if not all, are normally found inside beta-cells.
Type 1 diabetes - Autoantibodies to a zinc transporter, ZnT8 Slc30A8 is also a type 2 diabetes susceptibility gene… interesting…
Type 1 diabetes - Insulin is an early autoantigen in humans Antibodies to insulin are usually the earliest to be detected in high-risk infants.
Type 1 diabetes - Insulin is a ‘primary’ autoantigen in NOD mice
Type 1 diabetes - Triggers? Examples: • Viruses • Cow’s milk (insulin)
Type 1 diabetes - Mechanisms of -cell death Pancreatic beta-cells are specifically targeted in type 1 diabetes.
Type 1 diabetes - Mechanisms of -cell death Cytokines play an important role in beta-cell death in type 1 diabetes.
Type 1 diabetes - Mechanisms of -cell death
Type 1 diabetes - Mechanisms of -cell death
Type 1 diabetes - Mechanisms of -cell death
Questions or discussion Do any of these work in humans? What does that tell us?
?
Type 2 diabetes - Possible role for the immune system?
Ramlo-Halsted et al.
Type 2 diabetes - Possible role for the immune system?
Type 2 diabetes - Possible role for the immune system?
http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html
Type 2 diabetes - Resident macrophages are found in islets
Islet Macrophage
Type 2 diabetes - Macrophages are abundant in T2D islets
Questions or discussion If type 2 diabetes is affected by systematic inflammation, how can we use this information?
?
Dr. Jim Johnson, Ph.D. Assistant Professor, Dep t. of C ellular and Physiological Sciences and Dep t. of Surgery, University of British C olumb ia 5358 Life Sciences Building Lab W eb site: www.diab etes.ub c.ca Office: (604) 822-7187 E-mail: [email protected] c.ca
Immunology in Endocrinology Outline and Objectives: 1) 2) 3) 4) 5) 6)
Immunology basics - self versus non-self Immunology basics - specific cell types Immunology basics - T-cell activation Immunology in Endocrinology - Other diseases Immunology in Endocrinology - Type 1 diabetes Immunology in Endocrinology - Type 2 diabetes
Immunology basics - Self versus non-self ‘Immunity’ refers to the global ability of the host to resist the predation of microbes that would otherwise destroy it. Immunity has many facets, but the greatest dichotomy separates adaptive immunity (‘acquired immunity’) from innate immunity (‘natural immunity’ or ‘innate resistance’). A key element of immunity is the recognition of ‘self’ and of ‘nonself’. Errors in this recognition lead to autoimmune diseases, likely type 1 diabetes. A complex array of cell types control this process.
Immunology basics - Innate vs. Adaptive Immunity The immune system is typically divided into two categories--innate and adaptive--although these distinctions are not mutually exclusive. Innate immunity Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body. These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. The innate immune response is activated by chemical properties of the antigen. Adaptive immunity Adaptive immunity refers to antigen-specific immune response. The adaptive immune response is more complex than the innate. The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a "memory" that makes future responses against a specific antigen more efficient
Immunology basics - Cellular vs. Humoral Immunity
Questions or discussion Where are the ‘weak links’ in the immune system?
?
Immunology basics - Specific cell types
Immunology basics - Hematopoietic stem cells
Questions or discussion What is the proof, in the lab or in the clinic, that these cells are truly stem cells?
?
Immune cell types
Immune cell types Red blood cell
Monocyte Neutrophil
Platelet
Immune cell types - B cells B lymphocytes (from Bursa of Fabricius) These cells are major antibody producers. •Plasma B cells are actively producing antibodies. •Memory B cells respond quickly following a second exposure to a specific antigen
Immune cell types - T-cells T-lymphocytes - mature in the thymus These cells are a major mediators of cell-mediated immunity.
T-lymphocytes - T-cell receptor T-lymphocytes talk with antigen-present cells using the T-cell receptor. The signal from the T cell complex is enhanced by simultaneous binding of the MHC molecules by a co-receptor. The co-receptor on helper T cells is CD4, which exclusively binds the class II MHC. The co-receptor on cytotoxic T cells is CD8, which is specific for class I MHC. The co-receptor not only ensures the specificity of the TCR for the correctly-presented antigen but also allows prolonged engagement between the antigen presenting cell and the T cell and recruits essential molecules (e.g., LCK) inside the cell that are involved in the signaling of that activated T lymphocyte.
T-lymphocytes - T-cell activation
T-lymphocytes - T-cell activation signalling pathways
T-cell activation - The role of Ca2+ signals A cytosolic Ca2+ signal is an essential early event in T cell activation.
T-cell activation - The immunological synapse T-cells ‘lock’ onto antigen presenting cells via a ‘synapse’.
T-cell activation - The immunological synapse T-cells ‘lock’ onto antigen presenting cells via a ‘synapse’.
T-cell activation signals proceed the formation of the ‘synapse’.
T-cells - Immunosuppressant drugs block T-cell activation Islet transplant drugs: Tacrolimus (FK506) - blocks calcineurin Sirolimus (rapamycin) - blocks mTOR Daclizumab - antibody against IL-2R
T-cell activation - Shape changing
T-cell activation - signals controlling cytoskeleton reorganization
Questions or discussion Any questions on T-cell activation. What types of signal coding are involved?
?
Immune cell types - Subsets of T-cells Helper T cells - Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Cytotoxic T cells - Destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells. Memory T cells - A subset of antigen-specific T cells that persist after an infection. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+. Regulatory T cells - (a.k.a. suppressor T cells). These are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing fatal autoimmune disease. Natural Killer T cells - bridges the adaptive immune system with the innate immune system. NKT cells recognize glycolipid antigen presented by a molecule called CD1d, rather than MHC. Once activated, these cells initiate both cytokine production and release of cell killing molecules. T cells - possess a distinct TCR on their surface. 5% of all T cells. Autoaggressive T cells - characterized by CD40 expression, which is typically is associated with antigen-presenting cells. Th40 cells are expanded in autoimmune subjects.
Regulatory T cells - Help suppress responses when appropriate This subset of T cells is identified by the expression of CD4, CD25 and FoxP3.
Regulatory T cells - Help suppress responses when appropriate
Mechanism of bystander suppression. Tregs that are activated by DCs in an antigen-specific fashion release IL-10. Once released, IL-10 inhibits immune reactions not only against the initial antigen (dot) but also against other antigens (square, triangle) in a nonspecific fashion.
Questions or discussion Do antigen-specific Tregs have potential therapeutic value?
?
Immune cell types - Natural killer cells Natural killer cells These cytotoxic cells are a major component of the innate immune system. They release granules of perforin and granzyme that cause cells to undergo apoptosis.
Immune cell types - Macrophages Macrophage (greek for big eaters) These cells roam tissues looking for ‘foreign cells’ or dead cells. They also display antigens via MHC class II.
Immune cell types - Neutrophils Neutrophils are granulocytes, filled with neutrally-staining granules which contain enzymes that help the cell to kill and digest microorganisms it has engulfed. The neutrophil has a lifespan of about 3 days.
Non-segmented neutrophils are younger.
Immune cell types - Neutrophil targeting and tissue invasion
Immune cell types - Neutrophils communicate with other cells Through cell–cell contact and secreted products, neutrophils recruit and activate monocytes, dendritic cells (DCs) and lymphocytes, and products of monocytes, macrophages and T cells activate neutrophils. Tissue macrophages ingesting apoptotic neutrophils produce less interleukin23 (IL-23). IL-23 triggers T cells in secondary lymphoid tissues to produce IL-17. IL-17 triggers stromal cells in the bone marrow to produce granulocyte colony-stimulating factor (G-CSF). G-CSF promotes proliferation of neutrophil precursors and release of neutrophils into the circulation (see text for references). BLyS, tumour-necrosis factor-related ligand B-lymphocyte stimulator; CXCL12, CXC-chemokine ligand 12; IFN, interferon-; TNF, tumournecrosis factor.
Neutrophils - Release serine proteases with specific targets
Neutrophils - A movie
Questions or discussion What dangers are there for people who are ‘neutropaenic’? What could cause this?
?
Autoimmune diseases - A partial list •Type 1 diabetes (possibly also type 2 diabetes) •Graves’ diseases •Hashimoto’s diseases •Systemic Lupus Erythematosus (SLE) •Multiple sclerosis •Rheumatoid arthritis
Autoimmune diseases - Graves’ and Hashimoto’s diseases
Graves' disease is a thyroid-specific autoimmune disorder in which the body makes antibodies to the thyroid-stimulating hormone receptor (TSHR), leading to hyperthyroidism, or an abnormally strong release of hormones from the thyroid gland.
Chronic thyroiditis (Hashimoto's disease) is a slowly developing persistent inflammation of the thyroid which frequently leads to hypothyroidism, a decreased function of the thyroid gland. Middle-aged women are most commonly affected.
Autoimmune diseases - Systemic lupus erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic, usually life-long, potentially fatal autoimmune disease characterized by unpredictable exacerbations and remissions with variable clinical manifestations. In Lupus SLE there is a high probability for clinical involvement of the joints, skin, kidney, brain, lung, heart, serosa and gastrointestinal tract. African-Americans and Asians are disproportionately affected. There is a female to male sex bias of 8:1.
Autoimmune diseases - Multiple sclerosis
Multiple sclerosis is a central nervous system disorder marked by decreased nerve function with initial inflammation of the protective myelin nerve covering and eventual scarring. Symptoms and severity of symptoms vary widely and may progress into episodes of crisis alternating with episodes of remission.
Autoimmune diseases - Rheumatoid arthritis
Rheumatoid arthritis is a systemic autoimmune disease which initially attacks the synovium, a connective tissue membrane that lines the cavity between joints and secretes a lubricating fluid.
Questions or discussion What do autoimmune diseases have in common? What does this tell us?
?
Autoimmune diseases - Type 1 diabetes Type 1 diabetes is one of the most common and most expensive autoimmune diseases. Frequent urination Excessive thirst Unexplained weight loss Extreme hunger Sudden vision changes Tingling or numbness in hands or feet Feeling very tired much of the time Very dry skin Sores that are slow to heal More infections than usual Nausea, vomiting, and stomach pains
Type 1 diabetes - Diagnosis
Type 1 diabetes - A model autoimmune disease Type 1 diabetes: 1) is associated with marked infiltration of T-lymphocytes. 2) can be transferred from one mouse to another by auto-reactive T-cells. 3) can be impeded (in mice) by treatments that suppress the immune system Insulin / CD3+ T-cells
Type 1 diabetes - a model autoimmune disease
Type 1 diabetes - Natural history of disease progression
Type 1 diabetes - Genetic susceptibility IDDM 1 - HLA genes
•In humans, the 3.6-Mb (3 600 000 base pairs) MHC region on chromosome 6 contains 140 genes. About half have known immunological functions. •MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. •Thus, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. •The strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes.
Type 1 diabetes - genetic susceptibility IDDM 1 - HLA genes
MHC Class 1
MHC Class 2
Type 1 diabetes - genetic susceptibility IDDM 1 - HLA genes
Type 1 diabetes - genetic susceptibility IDDM 2 - insulin gene The IDDM2 locus contributes about 10% of the type 1 diabetes risk that is synergistic with HLA. The IDDM2 locus contains a sequence of repeated DNA called a variable number tandem repeats (VNTRs). There are three classes of VNTR in the insulin gene: • Class I has alleles that range from 26 to 63 repeat units - common in Caucasians (70% of alleles), confers risk. • Class II has alleles that average around 80 repeat units - rare. • Class III has alleles ranging from 141 to 209 repeat units - protective. The presence of at least one class III allele is associated with a 3-fold reduction in the risk of type 1 diabetes, compared with common I/I homozygote genotype. Because the VNTR occurs in a non-coding region, its influence on diabetes risk cannot be attributed to an alteration of the protein sequence. The VNTR probably affects the transcription of the insulin gene. Class III alleles are associated with 15-30% lower INS mRNA in the pancreas, but higher INS mRNA in the thymus. The thymus helps train the developing immune system by deleting autoreactive T cells. Because the longer VNTRs cause more insulin to be produced in the thymus, the detection and deletion of autoreactive T cells may be more efficient. This improved immune tolerance to insulin would lessen the risk of a future onset of type 1 diabetes caused by anti-insulin antibodies.
Chromosome 11
Questions or discussion Is there an alternative hypothesis for the effects of the insulin VNTR?
?
Type 1 diabetes - Human susceptibility genes IDDM 3-18
Type 1 diabetes - Genetically susceptible NOD mice
NOD mouse
Human
Mouse diabetes genes are denoted with lower case (i.e. iddm1-27).
Type 1 diabetes - Hundreds of cures for NOD mice
Questions or discussion Do any of these work in humans? What does that tell us?
?
Type 1 diabetes - Autoantibodies Most, if not all, are normally found inside beta-cells.
Type 1 diabetes - Autoantibodies to a zinc transporter, ZnT8 Slc30A8 is also a type 2 diabetes susceptibility gene… interesting…
Type 1 diabetes - Insulin is an early autoantigen in humans Antibodies to insulin are usually the earliest to be detected in high-risk infants.
Type 1 diabetes - Insulin is a ‘primary’ autoantigen in NOD mice
Type 1 diabetes - Triggers? Examples: • Viruses • Cow’s milk (insulin)
Type 1 diabetes - Mechanisms of -cell death Pancreatic beta-cells are specifically targeted in type 1 diabetes.
Type 1 diabetes - Mechanisms of -cell death Cytokines play an important role in beta-cell death in type 1 diabetes.
Type 1 diabetes - Mechanisms of -cell death
Type 1 diabetes - Mechanisms of -cell death
Type 1 diabetes - Mechanisms of -cell death
Questions or discussion Do any of these work in humans? What does that tell us?
?
Type 2 diabetes - Possible role for the immune system?
Ramlo-Halsted et al.
Type 2 diabetes - Possible role for the immune system?
Type 2 diabetes - Possible role for the immune system?
http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html
Type 2 diabetes - Resident macrophages are found in islets
Islet Macrophage
Type 2 diabetes - Macrophages are abundant in T2D islets
Questions or discussion If type 2 diabetes is affected by systematic inflammation, how can we use this information?
?
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