بسم الله الرحمن الرحيم
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بسم الله الرحمن الرحيم. Immunological markers in the pathogenesis of type 1 diabetes in Saudi children. Diabetes Mellitus (DM). Definition : a group of metabolic diseases that result from insulin deficiency, defect in insulin action, or both . DM is characterized by hyperglycemia

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بسم الله الرحمن الرحيم

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Immunological markers in the pathogenesis of type 1 diabetes in saudi children

بسم الله الرحمن الرحيم


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Immunological markers

in the pathogenesis

of type 1 diabetes in

Saudi children


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Diabetes Mellitus (DM)

Definition: a group of metabolic diseases

that result from insulin deficiency, defect

in insulin action, or both.

  • DM is characterized by hyperglycemia

  • patient may present with polyurea,

    polydipsia, weight loss, polyphagia,

    blurred vision.


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Etiological classification of diabetes

mellitus

Type 1 diabetes mellitus

Type 2 diabetes mellitus

Other specific types:

Genetic defects of beta-cell functionInfections

Genetic defects in insulin actionUncommon forms of immune-

Diseases of the exocrine pancreasmedicated diabetes

EndocrinopathiesOther genetic syndromes

Drug or chemical-induced sometimes associated

with diabetes

Gestational diabetes mellitus


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Type 1 Diabetes Mellitus

  • Forms 10% of diabetic cases

  • Chronic disease in children and young adults

  • >75% of type 1 DM patients develop

  • the disease before the age of 30 years.

  • High mortality

  • 95% are due to autoimmune destruction of

  • beta cells of the pancreas

absolute (not relative) insulin deficiency


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Epidemiology

  • Type 1 diabetes incidence  through out the world by 2%/yr.

  • The incidence varies widely according to geographic location,

  • environment and genetic background of the population

IDDM incidence in different countries

per 100,000 / year


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Aetiology of Type 1 Diabetes Mellitus


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Objectives:

a) To study the autoimmune pathogenesis

of type 1 diabetes in Saudi children

b) To establish the specialized tests for the

detection of autoantibodies in type 1

diabetes

c) To study 1st degree relatives of type 1

diabetes patients to establish the

degree of risk due to the presence of

these antibodies in genetically

susceptible individuals


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Subjects:

  • Cross sectional study of the frequency of

  • autoimmune antibodies in type 1 diabetes

  • Children:

    • Al Sulaimania Hospital

    • King Khalid University Hospital

    • King Abdulaziz University Hospital

  • The inclusion criteria:

    • Saudi type 1 diabetes patient

    • Diagnosis based on the diagnostic criteria of the

    • Expert Committee of Diabetes on June 1997

    • <15 yrs (diagnosis defined as the date when

    • insulin treatment first began)


Immunological markers in the pathogenesis of type 1 diabetes in saudi children

Study groups:

  • Type 1 diabetes patients, n= 194

    • (93 boys; 101 girls)

    • Median age 6 yrs (1-17 yrs)

  • Newly diagnosed (< 3 months)

  • n =69 (34 boys; 35 girls.),

  • Median age 7 yrs; (1-13 yrs)


  • Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Study groups . . . . . cont.

    2.First Degree Relatives (n=60):

    Median age 7.5yrs (8/12 – 20 yrs)

    Inclusion criteria:

    Saudi

    Below 20 yrs

    No history of endocrine disease

    3. Controls:n=50:

    Median age: 7 (1- 17 yrs)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Methodology:

    • The questionnaire designed to show

      • the following:

    • 1) Duration of the disease

    • 2) Family history of the disease

    • 3) Rank of the patient between his siblings

    • 4) Season at time of diagnosis

    • 5) History of infection prior to diagnosis

    • 6) Household income of the family


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Methodology . . . . . cont.

    • Blood sample:

      • 5 mls collected in non-heparinized

      • (red top) tubes

    Serum is separated by centrifugation

    & stored at –20°C


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Methodology . . . . . cont.

    • Antibody assays:

      ELISA kits (Biomerica) to detect the 3 autoantibodies :

      • ICA (Islet cell antibody)

      • GADA (Glutamic acid decarboxylase)

      • IAA (Insulin autoantibody)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Basic principle of ELISA

    • Microwells are coated with

      specific antigen

    • Serum which contain the

      antibodies was added

      and incubated

    405nm

     The wells were washed so

    what remains are the

    antigen-antibody

    complex

     Conjugate was added which

    will bind with the complex formed

    is then read at 405nm

     The resulting color


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Statistical Analysis:

    • Chi square and Fisher’s exact test, were used to determine distribution of individuals among groups.

    • Z-test of percents drawn from one sample and two samples.

    • P value <0.05 was considered significant.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    RESULTS


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Results:

    Results were grouped into:

    • Epidemiology

    • Frequency of autoantibodies in all

    • diabetic patients as compared to

    • controls

    • 3. Frequency of autoantibodies in newly

    • diagnosed patients

    • Frequency of autoantibodies in

    • relatives

    • 5. Special cases


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    1) The epidemiology of type 1

    diabetes in Saudi children

    • Sex

    • Age

    • Income

    • Season

    • Ranking

    • Infection

    • Family history


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    • The sex distribution among Saudi

    • type 1 patients

    194

    101

    (52%)

    (Girls)

    93 (48%)

    (Boys)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    • Age of onset of type 1 diabetes in

    • Saudi children

    Two peaks of disease incidence:

    First peak in early childhood (3- 4 yrs).

    Second peak at pubertal age (9-12 yrs)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    • Seasonal variation in type 1 diabetes

    • onset

    • Important epidemiological factors in the incidence of

    • type 1 diabetes.

    • A winter peak in type 1 diabetes incidence was reported in

    • several Countries (Spain, Sweden, Jordan and the Sudan).

    Relation of onset of type 1 diabetes to environmental

    temperature

    Season Number Percentage

    Hot(summer) 58 48

    Cold(winter) 40 32

    Mild(spring, autumn) 27 22

    Total177100


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    d) The relation of birth order in the family and the risk of developing type 1 diabetes

    Number of earlier studies showed that first born child has a higher risk for type 1 diabetes.

    • Similar result was reported by Bingley et al. (2000).


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    • The role of recent infection in

    • precipitating type 1 diabetes

    • Viruses are primary suspected environmental

    • factors associated with diabetes.

    • Coxsackie virus was isolated from pancreas of

    • a 10 yrs old previously healthy boy, who

    • presented with diabetic ketoacidosis.

    • 1/3 of in-vitro rubella cases develop type 1

    • diabetes.

    • The direct role of viruses in the destruction

    • of beta-cells is not yet known.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Relation of onset of type 1 diabetes and history of recent infection (n=157 )

    Similar result was also reported from Japan. While Venezuelan diabetic children gave history of infection prior to diagnosis.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    f) Relation of type 1 diabetes and

    monthly income of their families

    Risk of type 1 diabetes is related to social class ( Pop. Density;

    Educational Level; Residence and Income)

    Average family monthlyPercentage

    incomeNumber %

    < SR5000 64 36

    SR5000 – < SR10000 65 36

     SR10000 48 27

    Total177100

    Japan, USA and UK


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    g) Risk of family members

    • Type 1 diabetes has an element of familial inheritance.

    • Monozygotic 25-60%, dizygotic twins 5-15%.

    • Risk among families is 5-15% , 0.4% in general

    • population.

    Relation Number Percentage

    Father 9 4.6

    Mother 3 1.5

    Siblings 20 10.0

    Father & Sibling 3 1.5

    Mother & Sibling 0 0.0

    At least 1 affected

    relative 29 15.0


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    ANTIBODY SCREENING


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Importance of autoantibodies:

    • The autoantibodies serve as a sensitive marker in prediction of type 1 diabetes. With predictive value reaching 100% for young siblings with high antibody titers.

    2) They are more prevalent in healthy relatives of type 1 diabetes than the general population  they may provide clues to the etiology of the disease, thus contributing to the preventive or therapeutic modalities.

    3) They confirm the autoimmune origins of the disease in patients who are difficult to categorize. So they improve the classification of diabetes.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Diabetic autoantibodies

    • 1) ICA

    • 2) IAA

    • 3) GADA

    • IA2 antibodies

    • Heat-shock protein Ab

    • Carboxypeptidase H Ab


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Islet Cell Antibody (ICA):

    • ICA were first described in 1974 in 90% of

    • newly diagnosed type 1 diabetes patients.

    • ICA are formed against several islet antigens:

    • ganglioside, sulphatidase, sialoganglioside.

    • Immunohistochemical staining of cadaveric

    • pancreas by patient’s serum was the first

    • method.

    • Alternative method for ICA detection is ELISA.

    • Results:

    • ICA is present in 33% of the studied

    • population and in 6% of the control.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    28%

    In newly diagnosed patients:

    • Previous study on Saudi type 1 diabetes:

      • a higher frequency of ICA (56%)

      • sample size was too small (n=16)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Low frequency of ICA in newly

    diagnosed Saudi patient may

    be due to:

    • Low disease incidence in Saudi Arabia,

    • ( Japan )

    • An ICA negative form of the disease.

    • Ethnic differences.

    • An early negative sero conversion.

    • Different testing technique.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Insulin Autoantibodies (IAA):

    • Insulin is the only specific antigen in

    • diabetes.

    • IAA: defined as autoantibodies that bind

    • insulin and occur in insulin untreated

    • patients.

    • IAA is found in 35-70% of newly diagnosed

    • type 1 diabetes patients and is highest in

    • young individuals.

    • IAA can be measured by both RIA and

    • ELISA.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    52%

    • Result Insulin Autoantibodies (IAA):

    • 70% of the study population

    • only2% of the control

    • Newly diagnosed is 52%


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Glutamic Acid Decarboxylase Ab

    (GADA):

    • GAD is an enzyme controlling the biosynthesis of

    • inhibitory neurotransmitter -amino butyric acid

    • (GABA).

    • GAD is present in  cells and other cells, but only

    • GAD extracted from brain and islets is recognized

    • by the sera of type 1 diabetes.

    • GADA found in (60-80%) of newly diagnosed type

    • 1 diabetic patient, and in less than 3% of control

    • subjects.

    • GADA is found in other diseases and it is not

    • transient antibody.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    58%

    • Result:( GADA )

      • GADA is present in 60% of the study population.

    • 58% of newly diagnosed


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    The frequency of autoantibodies & age

    No statistical significant differences in the frequency of antibodies and different age groups.Similar to Swedish children.

    No relation between the frequency of the three

    autoantibodies and sex


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    The frequency of autoantibodies and

    history of recent infection:

    Vahasalo et al (1996): infection during the preceding year increases the frequency of both ICA and IAA at diagnosis.

    Significant


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    The frequency of autoantibodies and

    family history of type 1 diabetes:

    Similar negative finding was reported by Rewers and Norris (2002) for ICA and IAA.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Frequency of autoantibodies

    and the duration of the disease

    • IAA frequency increases after

    • 3 months.

    • ICAs have the same frequency for

    • more than 3 years.

    • GADA increase after 3 years.

    • Similar results for ICA and GADA

    • (Savola et al., 1998).


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Causes of persistence autoantibodies

    with longer duration of the disease:

    • Slow process of  cell destruction.

    • Structural and/or functional mimicry

    • between exogenous proteins and

    • beta cell antigen or both.

    • Minimal scale, continuous cell

    • regeneration.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Multiple autoantibodies:

    • One autoantibody is present in 32%

    • Two autoantibodies are present in 26%

    • Three autoantibodies are present in 17%

    • One or more autoantibodies are present

    • in 75%

    • literature reported higher value 90%


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Combination of autoantibodies:

    Antibodies No. of Cases Percent

    ICA 19 28

    IAA 36 52

    GADA 40 58

    ICA and/or GAD 43 62

    ICA and/or IAA 40 58

    GAD and/or IAA 51 74

    ICA and/or IAA and/or GADA 52 75


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Importance of combination of

    autoantibodies:

    • Combination of tests is more sensitive for

    • the prediction of type 1 diabetes than the

    • result of any single autoantibody.

    • These tests can be used successfully as

    • first line screening tests to detect high

    • risk individuals.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    FIRST DEGREE

    RELATIVES


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Relatives of patients with type 1

    diabetes:

    • First degree relative have 15-20% greater

    • risk of developing type 1 diabetes than the

    • general population.

    • Family studies showed that majority of those relatives who developed diabetes were positive for autoantibodies.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Relatives of patients with type 1 diabetes . . . . . cont.

    • Study and follow-up of first degree

    • relatives facilitate:

    • a) identification of pre-diabetic subjects

    • b)work out the predictive value of different

    • disease markers

    • c)understand the pathogenesis of type 1

    • diabetes

    • d) encourage preventive measures.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    ICA in first degree relatives:

    • The risk of developing type 1 diabetes in

    • 10 yrs is 60-70% with higher ICA titer

    • (>80 JDFu).

    • ICA appears very early in life.

    • Due to difficulty in measuring ICA, it has

    • been replaced by other autoantibodies

    • combination.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    ICA in relatives:

    15%

    • Higher than European values (8% in Finland and Germany).

    • Increase disease incidence in SA;

    • technique variation Kohner et al., 1995


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    8%

    IAA in relatives:

    • The additional presence of IAA in non-diabetic relatives

    • positive for ICA  the risk of developing the disease.

    • 70% of subjects positive for ICA and IAA are insulinopenic.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    10%

    GADA in relatives:

    • GADA has 41% positive predictive value.

    • It is detected several years before the clinical onset

    • of the disease.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    The relation of frequency of autoantibodies with age in first-degree relatives

    • Kulmala et al., 1998.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Multiple autoantibodies in first degree relatives

    • 27% were positive for at least 1 antibody.

    • Higher than literature (Germany 12%; Italy 14%)

    • Only 5% were positive for multiple

    • antibodies. (Similar to European values)


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    SPECIAL CASES


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    During this study 2 relatives

    developed the disease

    Case #1

    5 yrs old male with an affected brother developed the disease, 3 months aftertaking the first blood sample.

    He was positive for IAA only.

    At time of diagnosis he also developed GADA.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    During this study 2 relatives

    developed the disease

    Case #2

    6 yrs old girl who developed the disease 3 weeks aftertaking the blood sample.

    Her blood sample was positive for IAA and GADA.

    This girl had an affected father, brother, and two sisters. Her mother also has hyperthyroidism.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Conclusions:

    • Detection of autoantibodies in pre-diabetic and newly

    • diagnosed patients facilitates the understanding of the

    • aetiopathogenesis of type 1 diabetes.

    • The frequency of the autoantibodies in the Saudi

    • newly diagnosed patients were as follows:

    • ICA=28%;GADA=58%;IAA=52%.

    • The frequency of ICA was very low compared to

    • European value, while the others were within the

    • reported values.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Conclusion . . . . . cont.

    • 75% of the Saudi newly diagnosed type 1 diabetes

    • expressed one or more of these autoantibodies at

    • time of diagnosis.

    • The combination of IAA and GADA identified 74%

    • of the newly diagnosed patients.

    • This combination improves the sensitivity of

    • predicting type 1 diabetes among relatives and the

    • general population.

    • During this study, two siblings developed the

    • disease and both were positive for IAA and GADA.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    RECOMMENDATIONS


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Recommendations:

    • Establishment of a national data-base

    • registry about type 1 diabetes in

    • Saudi Arabia.

    • Screening of first degree relatives and

    • depending on the size of the problem,

    • thereafter the general population.

    • Selection of the sensitive autoantibody

    • combination, such as: IAA & GADA,

    • added to it ICA or IA2 as a second step

    • for screening.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    Recommendations . . . . . cont.

    • Repeated analysis to increase the sensitivity

    • of autoantibody screening.

    • Follow-up of those at risk to find the

    • predictive value of each autoantibody and

    • their combinations.

    • All these data will be used for the planning

    • of future intervention trials.


    Immunological markers in the pathogenesis of type 1 diabetes in saudi children

    THANK YOU


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