Immunology sheet # 12 - Amani Rabab3a

بسم الله الرحمن الرحيم
Monday, December 27, 2010

We will continue speaking about autoimmune diseases.
Characteristics of Autoimmune Diseases
1- can be either systemic or organ specific , means that autoimmunity can be disseminated ,involvement more than one organ of the body , subsequently systemic manifestations are present . systemic immune pathology mediated by antibody
Example :- systemic lupus erythematosus (which is an autoimmune connective tissue disease that can affect any part of the body )
-rheumatoid arthritis
. or it is could be a single organ that is affected by inflammatory response of the autoimmune disease , generally speaking it is mediated by T-cells , however there are organ immune diseases are mediated by antibodies :
Examples: - antibodies against pancreas produce diabetes
-antibodies against receptors of thyroid stimulating hormone produce gravis diseases.

2- variable course between individuals or with the same individual . same individual undergoes aggravation or mild course of the disease , and different individuals the disease has variable course

3- Female preponderance , most autoimmune diseases affect females except diabetes affects male more than female. There are some diseases that affect both male and female with same percentage m but generally speaking autoimmune diseases affect female more.

4-Overlapping manifestations .
An individual who has autoimmune disease tends to have more than one disease . example : person who has Pernicious anemia may have also autoimmune thyroditis
Pernicious anemia ( " "فقر الدم الوبيل is one of many types of the larger family of megaloblastic anemias. It is caused by loss of gastric parietal cells, and subsequent inability to absorb vitamin B12.)
Manifestations tend to overlap . it is difficult to judge on the clinical base whether this is for example rheumatoid arthritis or another connective tissue disease . so we have to detect the target organ by looking for specific antibodies or T-cells that mediate the autoimmune disease .
5- Immunosuppression . autoimmune disease are associated with both immune suppression and immune deficiency .autoimmune diseases are characterized by increase the activity and over expression of effector mechanism by increase the rate of immune suppression and immune deficiency as if the general mechanism is disregulated.

Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent ,so the patient susceptible to have autoimmune disease , and also he may not to respond to vaccines properly.
6- Diverse immunopathology. Immune pathology means the mechanism immune destruction of tissues as a result of :cytotoxic T-lymphocytes , macrophages , T helper cells that mediate late hypersensitivity reaction or antibodies that either cause immune complexes or activation of antibody dependant cell mediated cytotoxicity . so there are diverse mechanisms that mediate the pathogenesis of autoimmune disease .
7- constant antigens. All immune diseases are associated with generation of immune response in the form of antibodies or sensitized T cells for specific antigen. If autoimmune disease result from recognition of many antigens as foreign, and subsequently generation of autoimmune response , and they be very common . Autoimmune diseases are common but not very common . so the autoimmune disease is a result of auto reactivity against specific antigen .examples : - auto antibodies against thyroid stimulating hormone in grave's disease
- Pancreas: Insulin-dependent diabetes mellitus (IDDM). The doctor also mentioned two other disease, but I could not hear them at all .
So the antigen is the same in all individuals . the target antigen responsible for evoking of autoimmune disease is the same in all individual regardless of age , predisposing factor or genetic etc. the target antigen the same .
8- Genetic susceptibility. It has been established that in certain diseases are associated with certain genes , it is not a single gene affected , usually more than one gene . This is usually in HLA antigen , MHC molecule is responsible for generation immune response . so the individual with HLA antigen has high percentage of certain autoimmune disease .
for your knowledge :The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes reside on chromosome 6, and encode cell-surface antigen-presenting proteins and many other genes. The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplantations. The major HLA antigens are essential elements for immune function. Different classes have different functions.
Example: Ankylosing spondylitis with HLA-B, but more are associated with DR antigen , which are antigens in DR region of class ll MHC
diabetes mellitus with D3,D4
Arthritis with DR3
FOR YOUR KNOWLEDGE :Ankylosing spondylitis " الْتِهابُ الفَقارِ المُقَسِّط,الْتِهابُ الفَقارِ الرُّوماتويديّ‎ "(AS, from Greek ankylos, bent; spondylos, vertebrae), is a chronic, inflammatory arthritis and autoimmune disease. It mainly affects joints in the spine and the sacroilium in the pelvis, and can cause eventual fusion of the spine.
9- Role of environmental factors .
- It is related to infection , many viral infections are associated with autoimmune disease , bacterial infection " like streptococcus , glomerulonephritis etc" . these factors either infect immune cells themselves or they have antigenic determinant that are similar to self , that's why product of immune response that target these organism as consequence that they target self tissues that cross react which are similar to these environmental factors
-exposure to certain drugs mediate formation of immune complex
-foreign proteins , like serum prepared in horses in diphtheria , associated with late hypersensitivity reaction type 3 due to production of antibodies against certain self component .
-Autoimmune hemolytic anemia associated with drugs like : kolinine?, methyldopa that are given for hypertensive patients .
- toxins of organisms also induce autoimmune diseases .

Examples of Organ-specific autoimmune Diseases:
Thyroid gland
- Grave’s disease - auto antibodies against TSH receptor
- Hashimoto’s disease" داءُ هاشِيموتو "

(thyroiditis) – auto antibodies against thyroglobulin, so the thyroid gland is gradually destroyed by varity of cells and antibody mediated immune response .
Pancreas: Insulin-dependent diabetes mellitus (IDDM) against ilet cells or insulin receptors.

Adrenal gland
- Addison’s disease (Hypoadrenocorticism):'means adrenal glands produce insufficient steroid hormones
- Reduced production of glucocorticoids and/or mineral corticoids as the result of atrophy of the adrenal gland
Serum from humans suffering from Addison’s disease may contain auto-antibodies against adrenal cortex cells and the enzymes involved in steroid hormone metabolism.

SLE as an Example of Non organ-specific autoimmune Diseases "systemic lupus erythematosus"
Prototypic systemic autoimmune disease due to deficiency of T cells. Multiple autoimmune manifestations and generally high titer anti-nuclear antibody (seronegative cases have been described means antibody negative, so antibodies may not be detected in this condition). Human SLE is more prevalent in females than males with 9 to 1 ratio (estrogens is immune suppression in nature appear to aggravate the condition as does the hyperprolactinaemia of lactation) .hyperprolactinaemia is the presence of abnormally-high levels of prolactin in the blood.
The clinical presentation of SLE involves joints polyarthritis, mucocutaneous lesions like butterfly, skin rash , proteinuria involving the kidney . Proteinuria ( or , from protein and urine) means the presence of an excess of serum proteins in the urine due to antibodies aggregation in the base of the kidney . anemia/thrombocytopenia where RBCs are involved in necrotizing of certain antibodies and they become a target of immune attack .
Slides show the manifestations of systemic autoimmune disease with SLP : discoid skin rash , aggregation of antibodies in glomerulus's.
Rheumatic diseases in autoimmune diseases caused by rheumatoid arthritis , it is advanced case in the slide in which the small joints are affected due to repeated synovitis with joints deformities , in another types the condition may be minor not severe .
Female: Male Ratios in Some Autoimmune Diseases.
Generally female are at higher incidence for autoimmune disease than males except in diabetes mellitus is higher among males than females .
- Multiple sclerosis 2:1
- Myasthenia gravis 2:1
- Diabetes 2:1
- Rheumatoid arthritis 4:1
- Graves’ disease 7:1
- SLE 9:1
- Hashimoto’s disease 50:1
For your knowledge : myasthenia gravis in which the circulating antibodies block neuromuscular junction in post synaptic neurons so patient becomes weak and fatigue.

Another figure shows the incidence of autoimmune diseases is higher in females like : myasthenia gravis , thyroid disease , scleroderma "disease characterized by hardening of the skin and connective tissue".
As you see in the figures , these percentages are statistic which are obtained from American and European that may vary.

Immunopathologic Mechanisms
 Tissue destruction: in diabetes; CTLs" cytolytic T lymphocytes " destroy insulin-producing B-cells in pancreas
 Antibodies block normal function: in myasthenia gravis; Ab "antibodies " binds acetylcholine receptors
 Antibodies stimulate inappropriate function: in Graves’ disease; it is called stimulatory hyper sensitivity where Ab binds TSH receptor, mimics thyroid-stimulating hormone and activates unregulated thyroid hormone production, , so thyroditis with hyper production, because in some cases there is thyroditis with hypo production
 Antigen-antibody complexes affect function: in Rheumatoid arthritis; IgM specific for Fc portion of IgG and IgM-IgG complexes deposited in joints leading to inflammation.

Autoimmune disease can be classified as :
1- diseases mediated by antibody against cell surface receptors :
- myasthenia gravis
- grave's disease
- insulin resistance diabetes
- hypoglycemia

2- immune complexes disease "type 3"
- sub acute bacterial endocarditis
- mixed essential cryoglobulinemia can be seen in hepatitis type b or c
for knowledge : Cryoglobulinaemia is a medical condition in which the blood contains large amounts of cryoglobulins - proteins that become insoluble at reduced temperatures. Cryoglobulins typically precipitate at temperatures below normal body temperature (37 degrees Celsius) and will dissolve again if the blood is heated. Cryoglobulinemia can be associated with various diseases such as multiple myeloma and hepatitis C infection.

- SLE where immune complexes deposit any where in the body

3- T cell mediated diseases , type 4
- insulin – dependent diabetes mellitus , pancreatic B cells are the antigen
- rheumatoid arthritis , synovial joints antigen result in joint inflammation and destruction .
- multiple sclerosis , target is myelin basic proteins
- celiac disease ,"الداء البطني "gluten modified by tissue transglutaminase result in severe malabsorption especially in children that have hypersensitivity to wheat .
for knowledge celiac disease intestinal digestive disorder caused by excessive sensitivity of the small intestine to gluten
Genes and Autoimmunity
 The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.

 Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene

In the figure HLA are reflection of genes , and HLA allotypes are products of genes
Relative risk means: the chance for development of the disease in an individual who carries the gene for another individual who does not carry that gene
Examples : - ankolysing spondylitis with gene B27 has been affected and relative risk for individual who carries this gene is greater than 150 , but who does not carry this gene the risk is less than 150 may be 90.
- Narcolepsy ,gene DQ6 relative risk is more than 40
For knowledge narcolepsy is disease characterized by uncontrollable sleep attacks (Pathology)
- celiac disease and IDDM with same HLA allotypes DQ2 and DQ8.
- Sub acute thyroditis
- Multiple sclerosis
The dr read only the previous diseases.
The gene sometime is protected when it is less than one
Example : individual who has DR3 , he has the risk for diabetes, and who has DR2 the risk decreases , and if he is homozygous he is protected against diabetes .so the genetic association vary from one individual to another

Now related to environmental factors or the infection
Look to the last table the doctor only read the infections with consequences
Note: the presence of infection associated with HLA genes the chance increases .




Immunology of transplantation :
• Transplantation means : A process of taking cells like "brain cells , bone marrow cells " , tissues like " skin , blood " , or organs like " heart, lung, liver , kidney " (a graft), from one individual who is donor and placing them into a (usually) different individual who is recipient to replace diseased ones .

Classification of transplantation depending on the relation between donor and recipient :
1- autography ,when the tissues or cells are transplanted form one individual to the same individual . and it is two types :- auto topic when cells or tissues taken from one site and transplanted to the same site .example bone marrow cells
- heterotopic cells or tissues are taken from one site and transplanted to another site . example :blood vessels taken from veins in lower limb and transplanted in the heart.

2- syngrafts . when the tissues are obtained from individual to another individual that they are genetically identical , means the have the same genetics makeup . like identical twins , and it is also found in animals ; in mice after 20 generation .
3- allografts , the tissue is obtained from one individual and transplanted to another individual who are from same species and genetic dis-similar . and it is the most common type , because in availability of syngrafts , and it is very difficult to find two individuals with same genetics makeup .
4- Xenografts : when the tissues are obtained from a donor to recipient of different species . this type is rare but utilized . like heart baboon surgery, transplantation of liver from pigs . , heart valves and tendons these tissues are immune privilege means without immune response .

Transplantation is common , it has started in past history like blood transfusion that was a common cause of catastrophe pr death , due to sever hemolytic reaction . sometime they were taking the blood even from animals .
Transplantation is now very common like : kidney transplantation , bone marrow for cancer , brain cells to treat Parkinson disease and another CNS progressive diseases .
• The most important barrier for successful of transplantation is Genetic disparity between the donor and recipient represents. Since this dissimilarity will result an immune response mounted by recipient against donor , or sometimes it is by donor against recipient tissues ; which is known as grafts …?? disease . so the major factor that successful of transplantation depends is genetic disparity which is known as graft rejection . In graft rejection the immunological classical concepts can not be applied to understand the field of transplantation . normally , when we inject an antigen like vaccine and follow what takes place , this is known as immune response . but in graft rejection it is different and we put it in different category.
• Two distinctive features of graft rejection :
1- very strong because the response against tissue antigens "huge amounts of antigens "
2- APCs those of the donor and recipient .


Normally when we inject the antigen to human no more than 10power to -5 of lymphocytes are activated , but in the case of tissue antigens this could be 10% of total lymphocytes = 10power to -1 and compare this with number for antigen response the difference is almost 100,000 more in tissue response.

Graft rejection , mechanism for initiation of the immune response :
• Direct presentation of Alloantigens
- T-cells can recognize allogeneic MHC antigens directly without the usual requirement of processing and presentation by APCs.


• Indirect Presentation of Alloantigens
- The recipient APCs present shed donor class I and class II MHC antigens. As a consequence, CD4+,CD8+,B cells and other effector mechanisms are activated.

Now imagine we have a cell carrying MHC class1 or 2 associated with antigen "in transplantation " , so this is familiar of the recipient immune system , and that is why there is a direct recognition , since this configuration is common it is known, and the immune system is educated to recognize the antigen with MHC class 1 or 2 . MHC molecules can not be expressed on the normal cells ( B cells , macrophages ) without having an antigen .


Now look at the figure ,














direct recognition : the donor APCs indirect recognition , the antigen will be taken
with MHC class 1 with antigen can by recipient APCs to T cells. And this type
be recognized by CD8 cells occurs in another immune responses.


So we have complex mode of T effectors pathway :
APCs of the donor with both MHC class 1 and 2
↓
Interact theoretically with CD8 + CD4
↓
Following activation of B cells, T cells , and monocytes they
Will enter the graft . MHC always triggers the response against the graft .

• Matching at MHC is possible only between relatives, but there are more than 30 types of antigen that are grouped in what is known as Minor Histocompatibility Antigens ; and these antigens will be presented by MHC class 1 and so recognized by CD8 response . that is why rejection absolute , except in identical twins , but there are maneuvers that try to promote survival of transplanted organ .

Mechanisms of Graft Rejection
• At least four distinct mechanisms have been identified so far and these mechanisms carry temporal implication , and the name of the rejection reactions is time sequence related : hyper acute means immediate, accelerated, acute, and chronic.

إعداد : أمــاني إسماعــيل الربابعة .
و آخر دعوانا أن الحمد لله رب العالمين

#12

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