Dr. Judith Greer's Presentation

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The immune system and scleroderma

Why is it so hard to find a cure for scleroderma?
* scleroderma is a very complex disease   * highly variable disease course
* large number of organs can be involved   * lack of well-defined clinical and biological markers of disease
* there are few effective ways to characterize the disease and to assess the severity of disease
* incomplete understanding of what causes scleroderma

Causes of Scleroderma
Genetic Factors: collagen genes, TGFB genes, HLA genes
Environmental Factors: silica, metal dust, solvents, CMV, hair dyes
Immunology Factors: CMV, HLA genes

Immunological factors in scleroderma
What is the immune system?
What is the normal role of the immune system?
What happens when the immune system doesn’t work properly?
How does the immune system go wrong in autoimmunity and particularly in scleroderma?

What is the immune system?
Bacteria, viruses, cancer cells

Innate and specific immunity
There are two arms to the immune response:
The innate response, which occurs very rapidly (hours to days). It is the first line of defence against bacteria and viruses, and is effective against many different organisms.
The adaptive response, which develops relatively slowly (days to weeks), but lasts a long time and is very specific in its effects.

Specificity & memory of the immune response
The B and T cells of the adaptive immune system have two important characteristics – specificity and memory
For example, if you are infected by the mumps virus when you are young, or are vaccinated against it, your B cells and T cells will remember this
These mumps memory cells wait around in the body and protect you against further infection by mumps, although they will not protect you against chickenpox or other viruses

Lymphatics & immunity
Immunity depends on continuous movement of immune cells through the body via the lymph vessels and the blood
The memory B and T cells sit around waiting in the lymph nodes for their specific target molecule to be brought to them by macrophages or dendritic cells
The B and T cells then divide rapidly and exit the lymph nodes to travel via the blood to the sites where they are needed
The immune system needs to be able to distinguish between “self” and “foreign”
T cells control this
New T cells from bone marrow go to the thymus to be “educated” about how to tell the difference between self and non-self
They then use several control mechanisms to stop immune cells attacking the body in which they live

Sometimes your immune system overreacts to foreign substances
In some cases, the immune response is inappropriately strong for the threat
This can cause unpleasant and potentially dangerous side effects (allergies, asthma)

Sometimes the immune system makes mistakes
One type of mistake is autoimmunity:  the immune system for some reason attacks your own body in the same way it would normally attack a germ.
Common autoimmune diseases include type 1 (juvenile) diabetes (attack on the insulin-producing cells in the pancreas) and rheumatoid arthritis (attack on the collagen in the joints)
Most scientists believe that autoimmunity plays a role in the disease process in scleroderma

Why does autoimmunity occur?
The education of the T cells in the thymus may be defective or tolerance mechanisms may break down
There may be changes in a molecule of the body so that the immune system no longer recognizes it as “self” or makes enhanced responses to it. This could be due to:
Virus infection (e.g. CMV, EBV, retrovirus)
Radiation/chemical exposure
Changes with ageing or in response to injury
Cross-reactivity between viral and self proteins

Why is it thought that autoimmunity plays a role in scleroderma?
Scleroderma shares many features with other autoimmune diseases
Anti-nuclear antibodies are present in the blood and T cells accumulate in affected organs
More common in women than men
More common in adults than children
Family members more likely to have other autoimmune diseases
Some genes involved in the immune system (the HLA genes) have been found to be associated with certain types of scleroderma
Symptoms similar to those of graft vs host disease

Autoantibodies in scleroderma
Most autoantibodies in scleroderma target the nucleus or nucleolus of the cells (where the genetic material is located)
Some of the anti-bodies are fairly specific for scleroderma, whereas others are also present in people with other autoimmune diseases
These autoantibodies are possibly just markers, rather than cause, of the disease … but maybe not

T cell autoimmunity in scleroderma
In the early stages of scleroderma, T cells accumulate in the skin and in the endothelium of blood vessels and produce factors called cytokines
One cytokine that appears to be central in the development of scleroderma is called transforming growth factor beta (TGFb) - it is produced by macrophages and neutrophils in addition to T cells and stimulates growth of fibroblasts
Genetic studies also suggest that people with scleroderma may be predisposed to produce increased levels of TGFb

How can we combat the immune system in scleroderma and other autoimmune diseases?
* Non-specific immunotherapy   * Immunomodulatory drugs   * Stem cell transplantation    * Specific immunotherapy

Problems with using non-specific immunomodulatory drugs
All of the targets of the immune-modulating drugs are molecules that are also required for normal functioning of the immune system
Many of the molecules targetted also have important effects in other systems, eg nervous system
If the immune-modulating drugs are used at effective concentrations they often have many unwanted side effects

Stem cell transplantation
Involves replacing the immune system
Has been trialled with some success in scleroderma
Involves mobilizing the bone marrow stem cells into the blood and harvesting them, then using chemotherapy to eradicate the existing immune cells
Once the immune system has been completely destroyed, the stem cells are re-introduced into the patient, in the hope that the new immune system that forms will not continue the autoimmune attack
Fairly high risk treatment

What type of research is being done on adaptive immune responses in autoimmune diseases?
T cells
Are they not being educated properly in the thymus, or not regulating self-reactivity?
What is their target?
How do we stop/change their response?
Are immune-related susceptibility genes affecting the response of the T cells
B cells/antibodies
How can pathogenic antibodies be removed?
How do we stop the B cell response?
Are the B cells controlled/helped by the T cells?

What sort of specific treatments are being investigated for autoimmune disease?
T cell vaccination – these aim to delete the clones of T cells that are inducing the autoimmune disease
Altered peptide ligands – these are synthetic peptides that are slightly changed from the sequence of the target molecule being recognized by the T cells
T cell receptor peptide vaccines – these act as a “decoy” for the disease-inducing T cells
Specific immunoabsorption of pathogenic antibodies

Gender and autoimmunity
Why are women more susceptible to many autoimmune diseases than are men?
Probably related to hormones, but may be related to genes on X-chromosome
During pregnancy, people with RA, MS, and some other autoimmune diseases usually go into remission – but, after delivering the baby, they often have a severe relapse
Attempts to cure or treat autoimmune disease by giving women male hormones have so far offered limited results, but newer studies on some factors produced during early pregnancy more promising
Some interesting findings in scleroderma suggest a role for foetal chimerism in disease pathogenesis

Microchimerism in scleroderma
Microchimerism is the presence of a small number of cells, genetically distinct from those of the host individual. The most common form is foetal chimerism, whereby cells from a fetus pass through into the mother.
women with scleroderma have 10 times more fetal cells circulating in their blood years after pregnancy than do mothers without the disease
If the genes that control the immune system match up in a specific way between grandmother and grandchild, the woman carrying cell types from both generations is 19 times more likely to come down with scleroderma
Are microchimeric cells mediating damage, facilitating tissue repair, or are they innocent bystanders?

The immune system probably plays a central role in scleroderma, but lots of details need to be studied further, including:
Identifying the targets of the T cells in people with limited or diffuse scleroderma
Determining whether some of the autoantibodies can play a pathogenic role
Determining whether people carrying different immune related genes develop different types of scleroderma
Role of microchimerism


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Please note: The new phone number for the Scleroderma Association of Queensland is 07 32773460. Our postal has changed too; it is PO Box 316, SALISBURY Qld. 4107. The new physical address of our office is 124A Evans Road Salisbury. If you would like to come and browse through some books in our library or have a chat or help, please visit on Wednesday between 9:30 and 12 midday.