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Endocrine I > Immune Mechanisms of Diabetes Lecture (Dr. Shnyra) > Flashcards

Immune Mechanisms of Diabetes Lecture (Dr. Shnyra) Flashcards

1
Q

Diabetes and Insulin

A
  • Diabetes was considered a TERMINAL CONDITION before Insulin was available for therapy
  • History created on January 11, 1922 when a 14 year old boy with T1D become the FIRST RECIPIENT OF INSULIN
  • Fredrick Grant Banting received the Nobel Prize for Insulin at the age of 32
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2
Q

Classification of Diabetes

A 
Diabetes Mellitus
Type I A:
1) Immune Mediated
2) Immune Etiology Distinction
3) Results in Insulin Dependence, with a loss of Beta Cells

Type I B:

1) Idiopathic
2) Unknown Etiologic Distinction
3) Results in Insulin dependent, with loss of Beta Cells

Type II:

1) Insulin Resistance and relative Insulin Deficiency is the Etiologic Distinction
2) Oral Hypoglycemic agents are Effective EARLY in Life

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3
Q

Genetics, Behavioral Factors, and Environment Triggers have impact on the development of T2D

A
  • Genetic susceptibility, sedentary lifestyle, high-fat diet, and psychological stress have Complementary effects on the Development of T2D
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4
Q

Changes in Immune Cell Populations in Adipose Tissue

A
  • LEAN Adipose Tissue contains GREATER portion of M2/M1 Macrophages
  • It also contains a Large Number of REGULATORY T CELLS (Treg Cells)
  • OBESITY Leads to Adipocyte NECROSIS and an INCREASE in M1 Macrophages
  • There is also a REDUCTION in TREG CELLS and an INCREASE in B CELLS, CD4+ Th1 Cells, and CD8+ T Cells
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5
Q

Obesity results in INFLAMMATION of ADIPOSE TISSUE

A
  • Lean Adipose tissue has ELEVATION Fractions of ANTI-INFLAMMATORY M2-like Macrophages and Treg Cells
  • The Local Environment is DOMINATED by ANTI-INFLAMMATORY CYTOKINES IL-10, IL-4, IL-13
  • Long term NUTRIENT EXCESS leads to APOPTOTIC and NECROTIC DEATH of Adipocytes
  • Upon Obesity, the ADIPOSE Tissue has a Mixed M1/ M2 Phenotype of ATMs, more Cd8+ T Cells than CD4+ Th1 Cells, and fewer Treg Cells
  • The Immune Cells promote CHRONIC INFLAMMATION through the production of Pro-Inflammatory Cytokine and Chemokines such as IL-1, TNF-Alpha, IL-6, CCL2, CCL3, and CXCL8 (IL-8)
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6
Q

What is Type I Diabetes

A
  • T1D is characterized by IMMUNE-MEDIATED Destruction of PANCREATIC Beta Cells resulting in INSULIN DEFICIENCY
  • Patentis with T1D are prone to KETOACIDOSIS, a Dangerously HIGH levels of Ketones in the Blood
  • Most cases are Characterized by AUTOANTIBODY markers of Beta Cells DESTRUCTION and Strong HLA ASSOCIATIONS
  • Type I Diabetes is a T CELL MEDIATED AUTOIMMUNE DISORDER
  • The onset of T1D is associated with INFILTRATION of the ISET of LANGERHANS by MONONUCLEAR CELLS and CD8+ T Cells. This infiltrate is termed INSULITIS!!!!!!!!
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7
Q

Which Factors Contribute to T1D?

A
  • T1D is the SECOND MOST FREQUENT Autoimmune Disease in Childhood
  • The LONG-TERM Micro and Macro-Vascular complication son Diabetes are associated with he leading causes of Disability and even Morality in Young Adults
  • T1D Development involved Genetic and Environment Factors, such as BIRTH Delivery Mode, use of Antibiotics, and Diet
  • Gut MICROBIOTA could be the Link between Environmental Factors, the Development of AUTOIMMUNITY, and T1D
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8
Q

Environment Factors of T1D

A
  • The CONCORDANCE RATE for T1D is MONOZYGOTIC TWINS is not 100% but about 30 to 50%, SUGGESTING ADDITIONAL NON-GENETIC INFLUENCES!!!
  • T1D INCIDENCE is INCREASING about 3% per year, the Rate too HIGH to be attributable to Changes in Susceptibility Genes
  • Evidence linking the Environment and T1D in humans in INDIRECT (EPIDEMIOLOGICAL and ANIMAL STUDIES)
  • There is also a 350 fold VARIATION in the INCIDENCE of T1D in different countries Worldwide
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9
Q

Breast Feeding vs Cow Milk

A
  • A variety of studies have shown AN INVERSE CORRELATION BETWEEN A DECREASE IN BREAST- FEEDING and the INCREASE IN TYPE1 DIABETES RISK
  • EARLY EXPOSE to Cow Milk in life (Ex: because of lack of Breast Feedgin) may CONTRIBUTE to T1D:
    a) IMMUNE TOLERANCE TO INSULIN might also be compromised by early exposer to Cow Milk which CONTAINS MUCH LESS INSULIN than does Human Milk
  • However, there is INCONSISTENCY in results of those studies which may attribute to:
    1) VARIATIONS in COMPOSITION of Milk

2) GEENTIC VARIATION in Cow Proteins
3) Vitiations in MILK-SENSITIVE DIABETES-PRONE INDIVIDUALS in Studies

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10
Q

Diet Factors

A
  • WHEAT GLUTEN is a POTENT DIABETOGEN
  • The risk of T1D is HIGHER in patients with GLUTEN SENSITIVE ENTEROPATHY
  • Other Environmental factors linked with T1D include VITAMIN D, an Immune Modulator and Suppressant
    a) The NORTH-SOUTH Gradient of T1D incidence in Europe, with Lower Mean SUNSHINE HOURS in the North
  • PSYCHOLOGICAL STRESS has also been suggested as a Trigger for Diabetes, but data are sparse and Inconsistent
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11
Q

Hygiene Hypothesis and T1D

A
  • Exposure to a variety of Infectious Agents during early Childhood might be PROTECTIVE in T1D as well
  • A Constant INCREASE in the Incidence of T1D contrasted by a GRADUAL DECREASE in the Incidence of INFECTIOUS DISEASES such as TB, Mumps, Measles, Hepatitis A, and Enterovirus Infections
  • A Variety of studies have shown an INVERSE CORRELATION between a Decrease in Breast-Feeding and the INCREASE in T1D Risk.
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12
Q

Role Infections in T1D

A
  • STREPTOZOCIN and BIFILOMYCIN A1 form Streptomycin are CYTOTOXIC FOR BETA CELLS
  • BACTERIA may also act as ADJUVANTS for the Immune Response to food Ags
  • VIRUSES may act against Beta Cells by a Mechanisms that include:
    a) Direct CYTOTOXICITY
    b) Triggering of an Autoimmunity by MOLECULAR MIMICRY
  • Viruses which have been Implicated with T1D:
    a) MUMPS
    b) RUBELLA
    c) Cytomegalovirus
    d) Enteroviruses
    e) Retroviruses
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13
Q

Genetics of T1D

A
  • Familial CLUSTERING in T1D
  • The RISK of developing T1D before age 20 years:
    a) 6% int he Sibling of an Affected Patient

b) 0.4% in General Population

  • The CONCORDANCE:
    a) 30 to 50% in Monozygotic Twins
    b) 10% in Dizygotic Twins
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14
Q

What genes determine T1D Susceptibility

A
  • Type 1 Diabetes is a MULTIFACTORIAL AUTOIMMUNE Disease
  • T1D patient with ant their relatives are at INCREASED RISK for OTHER AUTOIMMUNE DISEASE (Thyroid Autoimmunity and Addison’s Disease
  • There may be NO SPECIFIC DIABETES GENE, but….
  • Only specific “WRONG” COMBINATIONS of Normal POLYMORPHISMS!!!!
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15
Q

What genes are Associated with T1D?

A
  • About 18 GENES of varying potency are associated with Susceptibility to T1D

MOST SIGNIFICANT
1) The HLA Region (the MHC Gene on CHROMOSOME 6): Presentation of INSULIN Ags for CD8+ T Cells

2) The INSULIN GENE (CHROMOSOME 11): Ag for Autoimmune Response
3) REGULATORS of Insulin Gene expression in the Thymus (AIRE)
4) The CTLA-4 GENE (CHROMOSOME 2): Regulation of Autoimmune REsponse

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16
Q

Role of HLA in T1D

A
  • HLA Alleles DQ2/ DQ8 and DR3/ DR4 are the HIGH-RISK Alleles
  • Alleles DQ2/ DQ8 (Haplotypes with DR3DQ2 or DR4DQ8) found in more than 90% OF INDIVIDUALS with T1D!!!!!!!!!
  • Heterozygous Genotypes DR3/ Dr4 are most COMMON IN CHILDREN diagnosed with T1D prior to the age of 5 (50%)
  • HLA Class II molecules that LACK ASP57 OF THE BETA CHAIN are often found among individuals with T1D
  • HAL Class II Haplotypes such as DR2/ DQ6 confer dominant PROTECTION
17
Q

The Insulin Gene (IDDM2)*****

Check Lecture

A
  • Mapped to a Region contains the VARIABLE NUMBER OF TANDEM REPEATS (VNTR) in the PROMOTER REGION of the Insulin Gene
  • the VTNR POLYMORPHISM is categorized into Class I, II, and II
  • The SUSCEPTIBLE CLASS I Alleles of the Insulin VNTR are associate with LOWE INSULIN mRNA SYNTEHSIS resulting in:
    a) Low Ag (Insulin) Synthesis

b) Low Ag Presentation in the Thymus
c) Failure of Deleting Self-Reactive CD8 T Cells
- The CENTRAL TOLERANCE is BROKEN with Class I Alleles

18
Q

Transcription AutoImmune Regulator (AIRE)

A
  • Transcriptional EXPRESSION of INSULIN in the Thymus is controlled by AIRE
  • Malfunctioning of AIRE results in LOWER LEVELS OF INSULIN mRNA in the Thymus
  • The Absence of Insulin results in FAILURE OF DELETING Insulin-Reactive T Cells and the CENTRAL TOLERANCE is Broken!!!!!!
  • AIRE is a CRITICAL Factor in the Induction of Central Tolerance against Insulin
19
Q

CTLA -4 Gene (IDDM12)

A
  • CTLA4 (Cytotoxic T Lymphocyte Antigen-4) is the SUSCEPTIBILITY LOCUS on Chromosome 2 to be associated with T1D
  • CTLA-4 (CD152) encodes a Glycoprotein that is a CD28 HOMOLOGUE and bind B7 PROTEIN (CD80/ 86)
  • CTLA-4 may COUNTER-REGULATE the CD28- Dependent TCR ACTIVATION of T CELLS
  • The Function of CTLA-4 is SUPPRESSION of T CELL ACTIVATION and activation of its APOPTOSIS
20
Q

Mechanisms of Action of CTLA-4

A
  • Engagement of CTLA-4 on a T Cell may deliver INHIBITORY SIGNALS that Terminate further activation of that cell (Cell-Intrinsic Function of CTLA-4)
  • CTLA-4 on Regulatory or responding T Cells binds to B7 Molecules on APCs or removes these molecules form the surface of APCs, making the B7 costimulators unavailable to CD28 and Blocking T Cell Activation
21
Q

CTLA-4 Controls the PERIPHERAL TOLERANCE

A
  • CTLA-4 competes with CD28 for binding CD80 leading to Cell-Cycle arrest that prevents Expansion of activated T Cells
  • Failure of T Cells to express the CTLA-4 gene due to Mutation may Contribute to ABERRANT IMMUNE RESPONSES seen in T1D
  • Soluble Recombinant CTLA4 (sCTLA4) has been used in Clinical Trials or TREATMENT of AUTOIMMUNE DISEASES
22
Q

CTLA-4 on the Board Exams

A

IN ACTIVATED T CELLS CD152 (CTLA4):

a) Biomes Sequestered within GOLGI
b) Binds to Appropriate MHC
c) Induces PROGRESSION through the Cell Cycle
d) Stimulate Transcription of IL-2 mRNA
e) BEGINS TO MOVE TO THE MEMBRANE AND BINDS CD80/CD86!!!!! (THIS IS THE ANSWER TO THE QUESTION!!)

23
Q

Autoantibodies in T1D

A
  • ISLE CELL AUTOANTIBODIES (ICA) are detected in Individuals with T1D are present with INCREASED FREQUENCY among individuals recently diagnosed with T1D
  • Autoantibody production APPEARS IN ADVANCE (Months to years) of the Metabolic Changes T1D can be used to predict Disease
  • Their present CONFIRMS a DIAGNOSIS of Type IA Diabetes
  • THE SPECIFICITIES of Several Identified ICA include:
    1) Glutamic Acid Decarboxylase (GAD65)

2) Insulinoma Antigen-2 (IA-2, TYROSINE PHOSPHATASE)
3) Insulin AutoAntibodies (IAA)

24
Q

Pathogenic Role of Auto-Abs

A
  • Despite the utility of Autoantiboes for Diagnostic Purposes, their PATHOGEN CONTRIBUTION IS CONTROVERSIAL:
    a) T1D cannot be transferred using Serum from Diabetic Humans —-> PLASMAPHERESIS PRIVETS LITTLE THERAPEUTIC BENEFIT

b) T1D was reported in a 14 year old male with X LINKED AGAMMAGLOBULINEMIA

WHAT IS THE PATHOGEN ROLE?
- Autoantibodies MAY AFFECT THE TIME COURSE of Disease Development

25
Q

Autoantibodies

A
  • The presence of 2 OR MORE distinct Antibody specificities is HIGHLY PREDICTIVE of future T1D (Five year risk = 28- 66%)
  • When COMBINED WITH HLA typing, Autoantibody Screening is also USEFUL FOR PREDICTION disease in General Populations
26
Q

T1D

A
  • T1D is Th1-MEDIATED DISEASE!!!!
27
Q

Th1/ Th2 Paradigm

A
  • The T1D AUTOREACTIVE T CELLS belong to the Th2 SUBSET
28
Q

Pathogenic Role of T Cells

A
  • T Cells are ACTIVATED IN THE LYMPH NODES that drain the Pancreas
  • Once activated, ISLET Specific T Cells TRAFFIC TO THE PANCREAS where they PROLIFERATE and accumulate resulting in Organ Specific INFLAMMATION
  • LOCAL APCs capable of presenting Ag in the Context of CLASS II MHC molecules and Secreting IL-12 play an important role in the Pathogenesis if T1D
  • These PACs activate Ag-specific CD4 T CELLS and further stimulated IFN-GAMMA
  • IFN-Gamam INHIBITS Th2 CYTOKINE PRODUCTION (IL-4, IL-5, IL-10) and enhance IL-1Beta, TNF-Alpha, and free radical production of Macrophages which are all toxic to Islet Beta Cells
29
Q

Cell-Mediated Immunity and T1D

A
  • A counter regulatory role of Th1/ Th2 subsets would suggest that T1D WOULD NOT OCCUR WITH ASTHMA
  • However, ASTHMA IS MORE PREVALENT in Children with T1D than Non-Diabetes Children
  • What is the COMMON DENOMINATOR?: The Failure of Regulatory Mechanisms controlled by TREG CELLS
  • SUSCEPTIBILITY to T1D may be greatly enhanced when TREG CELLS FAIL TO PREVENT ACTIVATION/ Expansion of Auto-Reactive T Cells
  • Islet Specific Pathogenic Clones of T Cells are found in Healthy Individuals, but T1D i prevented and the PERIPHERAL SELF TOLERANCE is maintained by Treg Cells
30
Q

T Regulatory Cells

A
  • Treg cells can ACT locally IN TISSUES and draining LYMPH NODES
  • Treg cells become ACTIVATED BY LOCAL APC presenting Auto-Ag
  • Treg cells SUPPRESS APCs DIRECTLY through Cell- Cell interactions or INDIRECTLY (Cytokines or Chemokines)
  • Alternatively, Treg Cells might act directly on T CELL EFFECTORS
31
Q

Mechanisms of Action of Regulatory T Cells

A
  • Regulatory T Cells appear to suppress Immune Responses at MULTIPLE STEPS. They may also directly suppress B CELL ACTIVATION and Inhibit the Proliferation and Differentiation of NK Cells.
  • Although SEVERAL MECHANISMS of Suppression have been proposed, the following are the best supported by available data:
    1) PRODUCTION of the IMMUNOSUPPRESSIVE Cytokine IL-10 and TGF-Beta

2) REDUCED ABILITY of APCs to STIMULATE T CELLS. One proposed Mechanisms of this action is Dependent ob Binding of CTLA-4 on Regulatory Cells to B7 Molecules on APCs
3) CONSUMPTION of IL-2 because of the HIGH Levels of Expression of the IL-2 Receptor, these cells may absorb IL-2 and deprive other T Cell populations of tis Growth Factor, resulting in Reduced Proliferation and Differentiation of other IL-2 Dependent Cells

32
Q

Cd4+/ Cd25+ Treg Cells in T1D

A
  • ISLET Specific Ags are released and presented in PANCREATIC LYMPH NODES
  • The Ags can activate damaging CD4+ and CD8+ T CELLS
  • The Ags can also activate CD4+/ CD25+ T reg Cells
  • Treg Cells PREVENT ACTIVATION of both CD4+ and CD8+ T Cells
  • Treg Cells are shown to PREVENT DIABETES in NOD Mice (Non-Obese Diabetic)
33
Q

Key Concepts

A
  • REGULATORY T CELLS ARE IMPORTANT
  • The Loss of Treg in IPEC Syndrome leads to NEONATAL DIABETES:
    1) IMMUNODYSREGUALTION, POLYENDOCRINOPATHY, ENTEROPATHY, X-Linked SYNDROME, a rare disease linked to the Dysfunction of the TRANSCRIPTIONAL ACTIVATOR FOXP3
    2) FoxP3 (Forehead box P3) is a SPECIFIC MARKERY of Natural T REGULATORY CELLS
  • FOXP3 appears to Function as the MASTER REGULATOR in the DEVELOPMENT and FUNCTION of Regulatory T Cells
34
Q

Key Remaining Questions in T1D

A

BASIC SCIENCE:
- What genes determine Type 1A Diabetes SUSCEPTIBILITY?

  • What triggers or Suppresses the activation of Autoimmunity?
  • What are the MAJOR TARGET Molecules and is there a primary Auto-Ag?
  • What are the EFFECTOR MECHANISMS for Islet Destruction?

CLINICAL
- Is Type 1A Diabetes PREDICTABLE?

  • Is the rate of PROGRESSION to over Diabetes Predictable?
  • Is Type 1A Diabetes PREVENTABLE?
35
Q

Three Major Islet Auto-Ags in T1D

A

1) INSULIN/ PROINSULIN:
a) Tissue Distribution:
- Beta Cells, Islet of Langerhans

b) Function:
- Regulator of Blood Glucose

c) PREVALENCE of AUTOANTIBODIES at DIAGNOSIS
- 50 to 70%

d) Comments:
- Most PREVALENT in Children with Type 1 DM

2) GLUTAMIC ACID DECARBOXYLASE -65 (GAD65)
a) Tissue Distribution:
- Endocrine Cells in Islets of Langerhan
- Central and Peripheral Nervous System

b) Function:
- GABA Synthesis

c) PREVALENCE of AUTOANTIBODIES at DIAGNOSIS
- 60 to 80%

d) Comments:
- Most prevalent in ADULT-Onset Type 1 DM

3) ISLET PROTIEN TYROSINE PHOSPHATASE (PTPs) IA-2 and IA-2Beta (Phogrin)
a) Tissue Distribution:
- Endocrine Cells in Islets of Langerhans
- Central and Peripheral Nervous System

b) Function:
- Unknown

c) PREVALENCE of AUTOANTIBODIES at DIAGNOSIS
- 40 to 60%

d) Comments:
- None

Endocrine I (13 decks)

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