Immune Mechanisms of Disease

Question 1

etiology and clinical distinctions of T1D

Answer 1

i. Type 1—beta cell destruction
1. Immune mediated
a. Etiology: immune
b. Clinical distinctions: results in insulin dependence, with loss of beta cells
2. Idiopathic
a. Etiology: unknown
b. clinical distinctions: results in insulin dependence, with loss of beta cells

Question 2

etiology and clinical distinctions of T2D

Answer 2

1. etiology: insulin resistance and relative insulin deficiency
2. clinical distinctions: oral hypoglycemic agents are effective early in the disease
3. genetics, behavioral factors, and environmental triggers have an impact on the development of T2D:
   a. genetic susceptibility, sedentary lifestyle, high fat diet, and psychological stress, smoking/alcohol

Question 3

other types of diabetes–etiology and clinical distinctions

Answer 3

1. etiology: specific genetic defects, pancreatic disease, endocrinopathies, chemical induced, infection related, immune mediated forms, genetic syndromes
2. clinical distinctions: specific mutations identified and defined clinical syndromes

Question 4

changes in immune cell populations in adipose tissue with Diabetes

Answer 4

i. lean adipose tissue contains a greater proportion of M2/M1 macrophages
1. also contains a large number of regulatory T cells
2. local environment is dominated by anti inflammatory cytokines IL10, IL4, IL13
ii. long term nutrient excess leads to apoptotic and necrotic death of adipocytes
iii. obesity leads to adipocyte necrosis and an increase in M1 macrophages
1. there is also a reduction in Treg cells and an increase in B cells, CD4 Th1 cells, and CD8 T cells
a. adipose tissue has a mixed M1/M2 phenotype, more CD8 T cells than CD4 Th1 cells, and fewer Treg cells
2. immune cells promote chronic inflammation thru the production of pro inflammatory cytokines and chemokines such as IL1, TNF alpha, IL6, CCL2, CCL3, CXCL8 (IL8)

Question 5

T1D general–what cells involved? what are its prone to? what characterizes most cases?

Answer 5

i. T1D is characterized by immune mediated destruction of pancreatic beta cells resulting in insulin deficiency
ii. Pts with T1D are prone to ketoacidosis—dangerously high levels of ketones in the blood
iii. Most cases are characterized by autoantibody markers of beta cell destruction and strong HLA associations
iv. T1D is a T cell mediated autoimmune disorder
v. The onset of T1D is associated with infiltration of islets of Langerhans by mononuclear cells and CD8 T cells
1. This infiltrate is termed insulitis

Question 6

which factors contribute to T1D?

Answer 6

1. T1D is the second most frequent autoimmune dz in childhood
2. Long term micro and macro vascular complications of diabetes are associated with the leading causes of disability and even mortality in young adults
3. T1D development involves genetic and environmental factors, such as birth delivery mode, use of antibiotics, and diet
4. Gut microbiota could be the link b/w environmental factors, the development of autoimmunity, and T1D

Question 7

breast feeding vs. cow milk with T1D

Answer 7

a. inverse correlation b/w a dec in breast feeding and the inc in type 1 diabetes risk
b. early exposure to cow milk in life due to lack of breast feeding may contribute to T1D
i. Immune tolerance to insulin might also be compromised by early exposure to cow milk which contains less insulin than human milk
c. however, there is inconsistency in results of those studies which may be attributed to:
i. variations in composition of milk
ii. genetic variation in cow proteins
iii. vitiations in milk sensitive diabetes prone individuals in studies

Question 8

wheat gluten
vitamin D
psychological stress
and T1D

Answer 8

a. wheat gluten is a potent diabetogen
i. the risk of T1D is higher in patients with gluten sensitive enteropathy
b. other environmental factors linked with T1D include vitamin D, an immune modulator and suppressant
i. north south gradient of T1D incidence in Europe with lower mean sunshine hours in the north
c. psychological stress has also been suggested as a trigger for diabetes, but data are sparse and inconsistent

Question 9

hygiene hypothesis and T1D

Answer 9

a. exposure to a variety of infectious agents during early childhood might be protective in T1D as well
b. a constant increase in the incidence of T1D contrasted by a gradual decrease in the incidence of infectious dz, such as TB, mumps, measles, hepatitis A, and enterovirus infections
c. a varietay of studies have shown an inverse correlation b/w a dec in breast feeding and an inc in T1D

Question 10

role of infections in T1D

Answer 10

a. streptozocin and bafilomycin A1 from Streptomyces are cytotoxic for beta cells
b. bacteria may also act as adjuvants for the immune response to food Ags
c. viruses may act against beta cells by mechanisms that include:
i. direct cytotoxicity
ii. triggering of an autoimmunity by molecular mimicry

Question 11

viruses that have been implicated in T1D

Answer 11

i. mumps
ii. rubella
iii. cytomegalovirus
iv. enteroviruses
v. retroviruses

Question 12

which genes determine T1S susceptibility?

Answer 12

a. T1D is a multifactorial autoimmune dz
b. T1D patient with and their relatives are at increased risk for other autoimmune dz—thyroid autoimmunity and Addison’s Dz
c. No specific diabetes gene but only specific “wrong” combinations of normal polymorphisms
d. 18 genes of varying potency are associated with susceptibility to T1D
i. most significant:
1. HLA region—chromosome 6 MHC gene—presentation of insulin Ags for CD8 T cells
2. Insulin gene—chromosome 11—Ag for autoimmune response
3. Regulators of insulin gene expression in the thymus—AIRE
4. CTLA4 gene—chromosome 2—regulation of autoimmune response

Question 13

how is central tolerance to insulin established?

Answer 13

a. Negative selection—in the thymus, insulin Ags are presented within class II MHC

Question 14

role of HLA in T1D

Answer 14

a. HLA alleles DQ2/8 and DR3/4, are the high risk alleles
i. Alleles DQ2/8 (haplotypes either DR3DQ2 or DR4DQ8) found in more than 90% of T1D individuals
b. Heterozygous genotypes DR3/DR4 are most common in children diagnosed with T1D prior to the age of 5—50%
c. HLA class II molecules that lack Asp57 of the beta chain are often found among indivudals with T1D
d. HLA class II haplotypes such as DR2/DQ6 confer dominant protection

Question 15

insulin gene

Answer 15

IDDM2

a. Mapped to a region of tandem repeats
b. VTNR polymorphism is categorized into class I, II, III
c. Susceptible class I alleles of the insulin VTNR are associated with lower insulin mRNA synthesis resulting in:
i. Low Ag (insulin) synthesislow Ag presentation in the thymusfailure of depleting self reactive CD8 T cells
d. Central tolerance is broken with class I alleles

Question 16

CTLA4 gene

Answer 16

IDDM12

a. CTLA4 is the susceptibility locus on chromosome 2 to be associated with T1d
b. Encodes a glycoprotein that is a CD28 homologue and binds B7 protein (CD80/86)
c. May counter regulate the CD28 dependent TCR activation of T cells
d. Function of CTLA4 is suppression of T cell activation and activation of its apoptosis

Question 17

MOA of CTLA4 gene

Answer 17

i. Engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of the cell
ii. CTLA4 on regulatory or responding T cells binds to B7 molecules on APCs or removes these mcs from the surface of the APCs, making the B7 costimulators unavailable to CD28 and blocking T cell activation

Question 18

CTLA4 gene and peripheral tolerance

Answer 18

• it controls peripheral tolerance
  i. CTLA4 competes with CD28 for binding CD80 leading to cell cycle arrest that prevents expansion of activated T cells
  ii. Failure of T cells to express the CTLA 4 gene due to a mutation may contribute to aberrant immune responses seen in T1D
  iii. Soluble recombinant CTLA4—sCTLA4—has been used in clinical trials for treatments of autoimmune diseases

Question 19

Inactivated T cells, CD153 (CTLA4) begins to move to the membrane and binds…

Answer 19

CD80/86

Question 20

islet cell autoantibodies

Answer 20

detected in individuals with T1D are present with increased frequency among individuals recently diagnosed with T1D

Question 21

what confirms a diagnosis of Type1A diabetes?

Answer 21

1. Autoantibody production appears in advance of the metabolic changes of T1D and can be used to predict disease
   a. Their presence confirms a diagnosis of type 1A diabetes

Question 22

specifications of several identified ICA?

Answer 22

a. Glutamic acid decarboxylase—GAD65
b. Insulinoma antigen 2—IA1, tyrosine phosphatases
c. Insulin autoantiboes—IAA

Question 23

pathogenic role of islet cell autoantibodies?

Answer 23

a. Despite the utility of autoantibodies for diagnostic purposes, their pathogenic contribution is controversial:
i. T1D cannot be transferred using serum from diabetic humansplasmapheresis provides little therapeutic benefit
ii. T1D was reported in a 14 yo male with X linked agammaglobulinemia
b. What is the pathogenic role?
i. Autoantibodies may affect the time course of disease development

Question 24

what is predictive of future T1D?

Answer 24

a. Presence of 2 or more distinct antibody specificities is highly predictive of future T1D
b. When combined with HLA typing, autoantibody screening is also useful for predicting disease in general populations

Question 25

T1D is what kind of disease?

Answer 25

Th1 mediated

Question 26

Th1/2 paradigm and T1D

Answer 26

a. In T1D, autoreactive T cells belong to the Th1 subset whereas protective T cells are of the Th2 subset
b. Experimental adoptive transfer of bone marrow of autoreactive T cells causes T1D in recipient mice
c. Implicates the immune system rather than the target cells/organs in the pathogenesis of T1D

Question 27

pathogenic role of T cells and T1D

Answer 27

a. T cells are activated in the LNs that drain the pancreas
b. Once activated, islet specific T cells traffic to the pancreas where they proliferate and accumulate resulting in organ specific inflammation
c. Local APCs capable of presenting Ag in the context of class II MHC mcs and secreting IL12 play an important role in the pathogenesis of T1D
i. These APCs activate Ag specific CD4 T cells and further stimulates IFN gamma
ii. IFN gamma inhibits Th2 cytokine production (IL4, 5, 10) and enhance IL1 beta, TNF alpha, and free radical production by macrophages which all are toxic to islet beta cells

Question 28

cell mediated immunity and T1D

Answer 28

a. Counter regulatory role for TH1/2 subset suggests that T1D would not occur with asthma
i. However, asthma is more prevalent in children with T1D than non diabetic children
ii. What is common denominator? The failure of regulatory mechanisms controlled by T reg cells
b. Susceptibility to T1D may be greatly enhanced when Treg cells fail to prevent activation and expansion of autoreactive T cells
i. Islet specific pathogenic clones of T cells are found in healthy individuals, but T1D is prevented and the peripheral self tolerance is maintained by Treg cells

Question 29

T reg cells and T1D

Answer 29

a. Treg cells can act locally in tissue and drain LNs
b. Treg cells become activated by local APC presenting autoAg
c. Treg cells suppress APCs directly through cell to cell interactions or indirectly (cytokines or chemokines)
d. Alternatively, Treg cells might act directly on Tcell effectors

Question 30

MOA of Treg cells with T1D

Answer 30

i. 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
ii. although several mechanisms of suppression have been proposed, the followed are the best supported:
1. production of immunosuppressive cytokines IL10 and TGF beta
2. reduced ability of APCs to stimulate T cells—one proposed MOA is dependent on binding of CTLA4 on regulatory cells to B7 mcs on APCs
3. consumption of IL2–b/c of high level of expression of the IL2 receptor, these cells may absorb IL2 and deprive other T cell populations of this growth factor, resulting in reduced proliferation and differentiation of other IL2 dependent cells

Question 31

CD4/CD25 T reg cells in T1D

Answer 31

i. Islet specific Ags are released and presented in pancreatic LNs
ii. The Ags can activate damaging CD4 and 8 T cells as well as CD4/CD25 T reg cells
1. T reg cells prevent activation of both CD4 and CD8 T cells
2. T reg cells are shown to prevent diabetes in NOD (non obese diabetic) mice

Question 32

neonatal diabetes*

Answer 32

i. Loss of Treg in IPEX syndrome leads to neonatal diabetes
1. Immunodysregulaiton, polyendocrinopathy, enteropathy, X linked syndrome, a rare disease linked to the disfucniton of the transcriptional activator FoxP3
a. FoxP3 is a specific marker of natural T regulatory cells
b. FoxP3 appears to function as the master regulator in development and fcn of Treg cells