For Dr.Mansur Al-Yazji

General view• Human body functions are tightly regulated by the continuous

and complex functions of 2 systems:• Nervous system.

• Endocrine system

• The main difference between the tow systems is• Endocrine regulatory effects take time to develop and regulate body functions and

homeostasis in a long term fashion.

• CNS regulate acutely and its effects disappear after a short time period.

• Endocrine system is:• A group of glands that pour its secretions in the blood to affect body's tissues in a

specific quantized manner.

• It requires :

• Stimulus for secretion.

• The gland tissues.

• body's tissues expressing a specific receptors.

• Blood to transport hormones.

• Secondary signal transduction.

• Outcome:

• Effect>> according to the specified tissue that expressed the receptor and the manner it respond to the stimulus.

• May be increase or decrease in blood concentration of a substance.

General arrangement

Gland

pituitary

Hypothalamus

Stimulation Inhibition

Hypothalamus connects pituitary By portal and neural connections.

Hypothalamus secretes Releasing Hormones.

Releasing Hormones affects pituitary which in turn secretes Tropic hormones.

Several kinds of Tropic hormones affects all endocrine glands of the body.

The affected gland upregulate synthesis and release of its hormones.

Hormones released inhibit both pituitary and hypothalamus .

Endocrine system• Glands of the body:

o Pituitary.

o Thyroid and parathyroid.

o Suprarenal gland.

o Pancreas islets.

o Liver.

o Gonads (testicles and ovaries).

o Various distributed sub mucosal neuroendocrine system.

Con.• Glands of the body:

o Pituitary.

• Produce tropic hormones and control body’s endocrine system.

o Thyroid

• In response to TSH > Secretes thyroxin and triiodothyronine, which control body's metabolic rate, they are counter regulatory hormones.

o Suprarenal gland

• 2 part cortex and medulla.

• Cortex is our interest.

• In response to ASTH > Secretes Glucocorticoids and mineralocorticoids* and steroid sex hormones.

o Pancreas islets.

• Our interest is Beta cells, which respond to hyperglycemia by secreting insulin, the body’s right hand of regulatory hormones.

o Liver: not of our interest.

• Secretes somatomedien C in response to GH

o Gonads (testicles and ovaries).

• Secretes sex hormones in response to LH and FSH.

o Various distributed sub mucosal neuroendocrine system.

• Not our interest

• Secretes various mediators such as serotonin and histamine.

Abnormal• What is the relationship between immune system

and endocrine system?

Endocrine system

Immune deficiency

Autoimmune reactions

Only effect of Cushing's syndrome

Which always transient effect.

What are we going to introduce…

• Autoimmune hypophysitis.

• Graves and Hashomoto’s thyroiditis

• Autoimmune addison’s.

• Premature ovarian failure.

• Insulin dependent diabetes mellitus.

• Autoimmune polyglanduler syndrome.

Thyroid GlandAyman Abu Helal

Graves’ Disease

GRAVES DISEASE• IT IS CAUSED BY AN AUTOANTIBODY (CALLED

THYROID STIMULATING IMMUNOGLOBULIN, TSI) THAT

ACTS LIKE THYROID-STIMULATING HORMONE (TSH)

AND THAT CAUSES THE THYROID GLAND TO

PRODUCE EXCESS THYROID HORMONE

Graves’ disease• The most common cause of endogenous

hyperthyrodisim.

• Autoimmune disorder.

• Common between 20 and 40 years

• Woman, 0.5 per 1000.

• Associated with precence of certain HLA haplocytes (HLA-B8 & DR3).

PATHOGENESIS:• Antibodies may be present in the serum including TSH

receptor, thyroglobulin and thyroid peroxisomes.

• The autoantibodies to TSH receptor are central to

disease pathogenesis and includes:

1. Thyroid stimulating immunoglobulin: it’s IgG antibody

bind to TSH receptor and stimulating adenyl cyclase

with resultant increase released thyroid hormones.

2. Thyroid growth-stimulating immunoglobulins:

Directed aganist TSH receptor.

3. TSH binding inhibitor immunoglobuline: these anti-TSH

receptor antibodies prevent TSH from binding normaly

to it’s receptor on thyriod epithelial cell. In so doing

some forms of TBII mimic action of TSH resulting in

stimulation of thyroid epithelial cell activity wheras

other form may inhibit thyroid function.

HASHIMOTO’S THYRODITIS

Ayman Mohammed Abu Helal

HASHIMOTO’S THYRODITIS

• Hashimoto thyroiditis is the most common cause of

hypothyroidism in areas of the world where iodine

levels are sufficient.

• It is characterized by gradual thyroid failure

because of autoimmune destruction of the thyroid

gland

• This disorder is most prevalent between 45 and 65

years of age and is more common in women than

in men, with a female predominance of 10:1 to 20:1

Charachtarized histologically by:

1. colloid degeneration

2. a change of epithelial cell to askanazy cells

3. germinal center formation

4. lymphoid infiltration

5. fibrosis

PATHOGENESIS:

• The overriding feature of Hashimoto thyroiditis

is progressive depletion of thyroid epithelial

cells (thyrocytes), which are gradually

replaced by mononuclear cell infiltration and

fibrosis. Multiple immunologic mechanisms

may contribute to the death of thyrocytes

• The effector mechanisms for thyrocyte death

include the following:

• CD4+ T cells produce inflammatory cytokines such as IFN-g in the immediate thyrocyte milieu, with resultant recruitment and activation of macrophages and damage to follicles.

• CD8+ cytotoxic T cells may cause thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme granules or engagement of death receptors, specifically CD95

• Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediatedcytotoxicity (ADCC)

• Several chromosomal abnormalities have been associated with thyroid autoimmunity.

• For example, adults with Turner syndrome have a high prevalence of circulating antithyroid antibodies, and a substantial minority (~20%) develops subclinical or clinical hypothyroidism that is indistinguishable from Hashimoto thyroiditis. Similarly, adults with trisomy 21 (Down syndrome) are also at an increased risk for developing Hashimoto thyroiditis and hypothyroidism.

• There are reports that polymorphisms in the HLA locus, specifically the HLA-DR3 and HLA-DR5 alleles, are linked to Hashimoto thyroiditis, but the association is weak

Immunologic observations:

• The first autoantibody associated with hashimoto’s thyroditis was anti-thyroglobulin (Anti-Tg)

• Now it is detected by agglutination of red cells coated with Tg or radioimmunoassay or ELISA of the binding of anti-Tg to Tg.

• Anti-Tg is almost always IgG also small amount of IgA and IgM have been detected.

• Anti-Tg does not fix complement.

• Other antibodies have also been detected in patient with hashimoto’s thyroditis anti-microsomal antibody, usually of IgG class.

• Anti-M antigen is cocentrated toward the apex of thyroid epithelia cell.

• Anti-M antibodies fix complement and there for may be responsible for the lysis of thyroid cells in vitro by sera from thyroditis.

Autoimmune AddisonMohammed Saed Qeshta

Addison's disease• Endocrine disorder

• is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex.

• glucocorticoid and mineralocorticoid function.

• 90% of adrenal gland disorder.

• Manifestation appearant when 90% of cortex has been destroyed.

Risk factor• Race: is no association with race.

• Sex: Addison disease tends to be more common in females and children.

• Age: The most common age in adults is 30-50 years.

• Low incidence + more than in developedcountries.

CausesAddison's disease causes

Adrenal dysgenesis

(genetic)

(ACTH gene)

Impaired steroidogenesis Adrenal destruction

Autoimmune infection

Auto-immune Addison's

disease

Auto-immune Addison's disease• an autoimmune inflammation of adrenal glands,

resulting in their gradual destruction and inability to make sufficient amounts of adrenal hormones.

• May be isolated( alone ) or combination with other autoimmune disease such as APS-I and II(polyglandular autoimmune syndrome).

• Steriod synthesis.

• 80%

Auto-immune Addison's disease• The progression of addison disease divide

into five stage

• Stage 0:- normal adrenocortical function.

• Stage I :- high plasma renin activity (PRA) why?!!!!! with normal or low aldosderonelevel

• Stage II:- response to ACTH is impaired.

• Stage III :- ACTH elevated.

• Stage IV:- the Signe of disease is apparent. (Addison's disease is present).

Immune-pathogenesis

Adrenal antigens • The most common adrenal antibodies found in

Addison’s disease are directed against P450

enzyme which involved in steroid synthesis.

• P450 enzyme :-

1. 21-Hydroxylase(P450c21).

2. 17α-hydroxylase(p450c17).

3. Cholesterol side chain cleavage enzyme (P450scc).

Immune-pathogenesis• The pathogenesis of Addison's disease is not

well clear.

• very complex.

• combined with two or more of immune response.

• Several studies.

Immune-pathogenesis• Murine model.

• Histological :- extensive lymphocytic infiltration in cortex.

• In humans:- the same

• Mononuclear infiltration :-

1. Lymphocyte (mainly) .

2. Plasma cells.

3. Macrophage.

• Infection.

Immune-pathogenesis• Autoantibodies adrenal antigens

• How ?!!!!!!

• Adrenal antigen are represented on plasma

membrane.

Mechanism

Immune-pathogenesis• Antibody- mediated cytotoxic cellular response by T

lymphocyte.

• With MHC molecule

• Or T-cell sensation to adrenal antigen more than

antibody.

Role of MHC• At normal :- it represented on adrenal cells.

• At Addison's disease :- increase expression .

HLA polymorphism• Have the role on Addison's disease

APS IAPS IIIsolated Addison's

disease

A28

Weaker

than

other

A1,B8,

DR3and

DR4

A1,B8,

DR3and

DR4

HLA

genes

Note• The pervious table refer to Malaren's study

which have not been confirmed.

• Some HLA-DR genes (2,5, and 7) appear to protect against Addison's disease.

• CD86(B7) interaction with CTLA-4 (CD152) and inhibition rather than T-cell response.

• Immune escape (^ MHC-I, v MHC-II).

• CTLA-4 polymorphism .

Conclusion • The immune disorders which response to

Addison's disease are :-

1. T – cell + complement.

2. Autoantibody (IgG, IgA, IgM).

3. MHC molecules.

4. CTLA-4

Autoimmune Premature ovarian failure

By Ahmed Abd Almon’em

Dr. Mansur Al-Yazji

2009

Definitions:• POF is defined as the cessation of menses before the age of 40

years. It is characterized by primary or secondary amenorrhea, hypoestrogenism, and elevated gonadotropin serum levels.

• Resistant ovary syndrome (ROS) is proposed as a follicular form of POF, characterized by the presence of numerous primordial follicles in the ovary.

• POF in the presence of adrenal autoimmunity (2–10% of cases) is almost certainly an endocrine autoimmune disorder. However, the question whether an eventual true autoimmune POF occurs in the absence of adrenal autoimmunity is controversial.

• ROS may represent a rare case of autoimmune POF characterized by the presence of antibodies directed to the follicle-stimulating hormone (FSH) receptor (Ig-FSHR).

General description.• In general, women with POF have normal fertility before

the onset of the disorder.

• Primary or Secondary amenorrhea

• Not always irreversible condition : women with POF may exhibit sporadic ovulatory cycles in as many as 16% of cases. Moreover, several authors have reported pregnancies after the diagnosis of POF.

• despite these isolated cases, patients with POF are troubled mainly by

• infertility because of cessation of their ovarian function.

IMMUNOPATHOGENESIS• Association of POF with autoimmune disorders.

• Circulating antibodies to normal ovarian tissue in sera from patients with POF.

• Lymphocytic infiltrate in the ovaries of some patients with this disorder

POF Associated with Adrenal Autoimmunity

• Most characterized.

• Autoantibodies: these antibodies that recognize several types of steroid-producing cells of the adrenal cortex, testis, placenta, and ovary have been called “steroid cell antibodies” (SCA).

• They are from IgG class ,they are cytotoxic due to ability to fix complement.

• In ovary they attack theca and granulosa cells in maturing follicles.

• There antigen is suggested to be steroid synthesis enzyme.

• Antigens include:P450-side chain cleavage (SCC), P450-17-OH, and 3-hydroxysteroiddehydrogenase (3-HSD)

• May be associated with APS I, II but most commonly with Autoimmune Addison’s disease.

Cont. …• Histologic preparations are limited to hilar rejoin where

endocrine cells present while stoma is intact.

• This pattern of infiltration confirms that steroid-producing cells are a main target for the autoimmune attack.

• Immunocytochemical staining identifies

• the cells as polyclonal B cells, CD4+ and CD8+ lymphocytes (with a predominance

• of the former), macrophages, and occasional NK cells.

• The overall appearances are

• suggestive of an antibody-dependent cell-mediated cytotoxicity.

POF Not Associated with Adrenal Autoimmunity

• Some have POF without Autoimmune adrenal disorders, and SCA are almost undetectable.

• This case is not will recognized BUT,o Antiovarian antibodies were detected.

o Enolase may be the molecular target of these anti-ovarian antibodies.

o Reported antigenic ovarian structures include the oocyte, corpus luteum, theca cells, granulosa cells, zona pellucida …

• Nevertheless, the pathogenic role of these antibodies remains questionable.

• Rare inflammatory infiltrates in these patients.

• It might represent the end stage of an autoimmune process directed against ovarian antigens, after the inflammation has ceased.

Resistant Ovary Syndrome

• Patients sera contain antibodies directed to the FSHR itself or to a receptor-related membrane domain.

• These AB can inhibit the receptor by preventing binding of FSH.

• Some observations in these patients:o They present a fluctuation of serum levels of antibodies.

• Monitoring levels of them aids in selecting best time to start treatment.

o Some of these antibodies inhibit FSH binding irreversibly and others reversibly.

• Some patient may respond to FSH sublimation.

• (Ig-FSHR) were detected in a male patient with primary gonadal failure.

Type one diabetes mellitus

By: Khalid Shaheen

Definitions:• IDDM is a T-cell-mediated autoimmune disease. Its

etiology is multifactorial, involving several

predisposing genes and complex environmental

factors.

• Insulin dependency is explained by the complete

destruction of β cells, the insulin-producing cells in

the islets of Langerhans of the pancreas in patients

with longstanding disease.

• IDDM may be preceded by a long phase of non-

insulin-dependent diabetes (latent autoimmune

diabetes of the adult, or LADA).

CLINICAL PRESENTATION

• Mostly, IDDM starts suddenly in a previously healthy

individual, usually a child.

• Initial clinical symptoms include polyuria and

polydipsia as a consequence of osmotic diuresis

induced by glycosuria.

• Weight loss is observed, and in some cases

ketoacidosis, leading to coma.

• The biological hallmarks of the disease are

hyperglycemia and glycosuria.

• Note that Beta cell sampling in humans is not

allowed due to biopsy-induced pancreatitis.

THE β-CELL LESION:

NATURE OF EFFECTOR CELLS• Diabetes onset is preceded by periinsulinitis stage in

which anti T-cell receptors antibodies prevents disease emergence.

• This prophylactic treatment show success till 24-48 hours after onset.

• Certainly the above mentioned is applied only in mice models.

• These models gave us these results:o Auto reactive CD4+ and CD8+ T cells are required to initiate the disease.

o CD8+ cytotoxic T lymphocytes capable of destroying β cells in a FAS or a perforin-dependent manner

o CD4+ produce cytokines notably IL-1.

o Autoantibodies does not demonstrate a Beta cell killing in any how.

o But mice without B lymphocytes does not developed diabetes, so B cells may play an antigen presenting role here.

THE RUPTURE OF TOLERANCE

TO β-CELL ANTIGENS• Is IDDM Associated with a Defect in Intrathymic

Negative Selection?

• β-Cell-Specific T Cells Are Present in Healthy

Individuals but Do Not Attack β Cells.

• Driving of the Islet-Specific Response by β-Cell

Antigens Search for IDDM Autoantigen(s)

• The Role of Regulatory T Cells.

• Conclusion.

• ETIOLOGY OF IDDM

Is IDDM Associated with a Defect in

Intrathymic Negative Selection?

• Autoreactive T cells may be seen in periphery.

• They can then be stimulated by the corresponding

auto antigen when it is adequately presented to

them in the context of MHC molecules.

• Perhaps IDDM results from escape of some

autoreactive T lymphocyte from negative selection

due to lack of expression of β-cell autoantigens

(perhaps under the control of the AIRE gene) or to

partial expression of these autoantigens >>>

Genetic predisposition??? .

β-Cell-Specific T Cells Are Present in Healthy

Individuals but Do Not Attack β Cells.

• It is possible to derive T-cell lines and to produce T-

cell clones specific to various β-cell autoantigens

(insulin, glutamic acid decarboxylase, or GAD) in

healthy individuals without significant Beta cell

distruction.

• Just like the transgenic animals.

• This state of ignorance implies that development of

diabetes requires that autoreactive T cells be

activated to become pathogen.

Driving of the Islet-Specific Response by β-Cell Antigens

Search for IDDM Autoantigen(s)

• Diabetogenic T cells are rapidly exhausted in the

absence of β cells.

• Kinds of antigens : Insulin (or proinsulin), GAD, IA.2, a

tyrosine phosphatase, and IGRP.

• Insulin was recently proposed as the primary

autoantigen.

The Role of Regulatory T Cells

• Regulatory T cells slow down disease progression.

• These cells are :CD4+ CD25+, or CD4+ CD25-CD62L+

• Where there effect go?

• It is suggest that whether regulatory T-cell function

declines at the time of diabetes onset or whether it

is overridden by a burst of effector cells…

• Another possibility is that effector cells resist

regulation.

Summary• Collectively, these data suggest that the triggering of

diabetogenic T cells leading to diabetes onset is a

multifactorial event.o Autoreactive β-cell-specific T cells are initially present in the periphery, perhaps

in higher number than in non-diabetes-prone individuals.

o These β-cell-specific T cells are activated by ill-defined mechanisms.

o The local inflammation of the pancreas, perhaps of viral origin, enhances the expression of the molecules contributing to antigen recognition (MHC, co-stimulation adhesion molecules).

o The differentiation and the activation of effector cells are initially controlled by regulatory T cells, but the efficacy of the control progressively declines and clinical diabetes appears.

ETIOLOGY OF IDDM• Genetic Factors

• IDDM has a strong hereditary component

• Approximately half of this heredity is due to MHC

geneso HLA-predisposing genes are essentially HLA DR3 and DR4 or their DQ

counterparts.

• Non-MHC genes are also important:o Insulin and CTLA-4 genes.

• There are a number of HLA (DR2) and non-HLA-

protective genes that oppose the effect of

predisposition genes.

ETIOLOGY OF IDDM• Environmental Factors categories of environmental factors are:

triggering and protective.

• Triggering factors have proven to be elusive.:o Pancreatotropic viruses are the best candidates.

• a role for enteroviruses, notably Coxsackie B4.

o Viruses could act in two ways:

• Viral proteins could resemble certain β-cell autoantigens (antigen mimicry).

• More likely, the local inflammation induced by the virus enhances the immunogenicity of β-cell autoantigens.

• Cow’s milk proteins have been incriminated through antigen mimicry between a lactalbumin peptide and a β-cell autoantigen (p69) but the hypothesis remains to be confirmed.

• Human IDDM occurs frequently in countries or people with high socioeconomic levels who are protected from infections (better quality of water and food, better conditions of lodging, more common usage of vaccinations and antibiotics)

• However, the environment may have a protective effect.

• Mechanisms underlying the protective effect of infections on IDDM:o Homeostatic competition, bystander

o Suppression through the effect of regulatory cytokines, and toll-like receptor stimulation.

Antigen mimicry

Viral Considerations• The viral hypothesis was initially based on the temporal

relationship between defined virus infections and onset of overt diabetes.

• The infection could at most exacerbate the anti-islet response and accelerate disease onset.

• Detection of antiviral antibodies in type I diabetes Patients.

• It has thus been reported that the frequency of enterovirus infections studied using both serology and testing for the presence of enterovirus RNA was correlated with islet-specific autoantibodies in subjects at risk of developing type I diabetes.

• An increased T-cell response to Coxsackie B4 antigens was also observed in a recently onset diabetic patient.

Viral Considerations• Collectively, these data are compatible with a viral

etiology of type I diabetes ,even though the

diabetogenic virus is still unidentified.

• The etiological infection may take place many

years before clinical onset

• Several pancreatotropic viruses could operate

through nonspecific inflammatory mechanisms.

• Antigen mimicry is possible, but there is no good

evidence for this hypothesis in humans (except a

questionable homology between a Coxsackie B4

virus protein and GAD).

HLA expression

β cellβ cell

Class Ⅰ MHC

molecule

High expression of

Class Ⅰ MHC

molecules

Abnormal

expression of Class

Ⅱ MHC molecules

Virus infection

Environmental

influence

CD4+ T cell response

MHC Ⅱ abnormal

expression

• Host cell turns into

APC• MHC Ⅱ + Self-Ag

Activate CD4+ T cell

ApoptosisFas-FasL pathway

Cytokine secretionTh1 IFN-γ TNF-α

Macrophage IL-1β TNF-α

Th1/Th2 unbalanceTh0 Th1

www.themegallery.com

CD4+ T cell related response

• Th0 cells mainly differentiate into Th1 cells, causing Th1/Th2 unbalance.

o Th1 cells produce IFN-γ& TNF-α, inducing expression of Fas protein on islet βcell, and FasL expression on CTL or macrophage(IL-1β , NO, RNIs).

o IFN–γ can activate NK cell ,which then hurt the target cells (β cell) with specific Ag .

o IL-2 IL-12

• Th2 antagonizes Th1 effects.

o IL-4 and IL-10 can strongly inhabit Th-1 to produce IFN-γ, which can decrease the level of isletitis and improve β cells to produce insulin, to decrease the morbidity of IDDM

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O2NO

Co-stimu-

latory

signals

APC

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Tc

Perforin

Th1

IFN

MØ

IL-1β

TNF

IsletPancreatic

lymph node

Th1

T- and B-cell

clonal ex-

pansion

APC

Granzyme

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Fas

FasL

RNIs Apoptosis

Fas

FasL