Chapter 16: Autoimmunity
Autoimmunity is evidence of an immune reaction to self components (self-antigen) in the absence of overt disease.
All of us have the capacity to mount autoimmune responses and in some circumstances, this may be a healthy, physiological reaction. This spectrum of the immune response from physiological may reach pathological range.
1898 Bordet did experiment on Rabbit. He transfused RBC to Rabbit and then took his serum and injected it to Rabbit but he could not get some positive response.
1929 Masugi succeeded in producing glomerulonephritis by injecting Rat kidney to Rabbit and Abs produced injected back to the same Rabbit.
1900 Paul Ehrlick gave the idea of harmful immunity “Horror autotoxicus”. His son 2 years old died due to the injection of diphtheria antitoxin serum after a few minutes.
Von Pirquet. First time introduce the concept about the collision of antigen and antibody.
Dixon. He gave the concept that regardless of the source of Ag if this result in tissue damage in the host is called autoimmune disorders.
Graber gave the concept that auto-Abs are of two types:
- 1st group have a biological function as taxis for transportation and disposable of Ag
- 2nd group Abs cause damage to the host.
It is believed that 5% of us will develop the autoimmune disease during our life.
The spectrum of Autoimmune Disease
There are organ-specific autoimmune diseases where Abs described against one or more specific cytoplasmic constituents, plasma membrane structure or secreted products of the cells.
While non-organ specific auto-immunity is directed against structures common to many tissues and found throughout the body e.g. nuclear components, mitochondrial proteins or constituents of the muscles. There may be overlaps of disease in the same group in some individual e.g. patient with Hashimoto’s thyroiditis have a much higher incidence of Pernicious Anaemia.
|Organ-Specific Non-Organ Specific|
|Hashimoto’s thyroiditis||Autoimmune hemolytic anemia||Good Pasteur syndrome||Primary biliary cirrhosis||Systemic lupus erythematosus|
|Primary myxedema||Idiopathic thrombocytopenic purpura||Myasthenia gravis||Chronic active hepatitis||Discoid lupus erythematosus|
|Thyrotoxicosis||Idiopathic leucopenia||Juvenile diabetes||Cryptogenic cirrhosis||Scleroderma|
|Pernicious anemia||–||Pemphigus Vulgaris||Ulcerative colitis||Rheumatoid arthritis|
|Addison’s disease||–||Sympathetic ophthalmia||Sjogren syndrome||–|
Table XXIII – Overlap Between Organ-Specific and Non-Organ Specific diseases
Overlap of Auto-antibodies
There is also an overlap of auto-antibodies in the same group e.g. patients with thyroid diseases, 30% may show at the same time antibodies against parietal cells while thyroid antibodies are found in 50% of pernicious anemia cases.
|1. Hashimoto’s thyroiditis||Thyroglobulin, second colloidal antigen|
|2. Primary Myxedema||Cytoplasmic microsome cell-surface|
|3. Thyrotoxicosis||Cell surface TSH receptor|
|4. Pernicious anemia||Intrinsic factor, parietal cell microsome|
|5. Addison’s disease||The cytoplasm of adrenal cells|
|6. Premature menopause||The cytoplasm of steroid producing cells|
|7. Juvenile diabetes||Islet cell cytoplasm, insulin|
|8. Good Pasteur Syndrome||The basement membrane of glomeruli and lung|
|9. Pemphigus Vulgaris||Desmosomes of the Prickle cell|
|10. Myasthenia gravis||Acetylcholine receptor of skeletal muscles and heart muscles.|
|11. Autoimmune Hemolytic Anaemia||RBC|
|12. Idiopathic thrombocytopenic purpura||Platelets|
|13. Primary biliary cirrhosis||Mitochondrial pyruvate dehydrogenase|
|14. Chronic active hepatitis||Smooth muscle nuclei. Cell surface Lipoprotein|
|15. Ulcerative colitis||Colon lipopolysaccharides|
|16. Sjogren syndrome||Duct, Mitochondria, IgG. Nuclei, Thyroid Ag|
|17. Rheumatoid arthritis||IgG, Collagen|
|19. Dermatomyositis||Nucleus, IgG|
|20. Systemic lupus erythematosus||
DNA, Nuclear proteins, IgG
Cytoplasmic proteins, formed elements of blood, clotting factors
Table XXIV – Autoimmune Diseases with their Possible Source of Antigen
The autoimmune disease could be considered to be one end of a spectrum of autoimmunity stretching from physiology to pathology. However the fact that the vast majority suggests that regulatory mechanisms are critical. This state of balanced, physiological autoimmunity may be described as Tolerance. On this basis, autoimmune diseases may be defined as a pathological process leading to the breakdown of Self-Tolerance.
Before the discussion of autoimmune diseases, we have to make a clear concept “What is Immunologic Tolerance” particularly “Self Immunologic Tolerance”.
Definition:- Immunologic Tolerance is a state in which an individual is incapable of developing an immune response to a specific antigen.
Immunologic Tolerance may be:
- Present at birth–prenatal tolerance.
- Acquired or present in adult age.
Immunologic Tolerance may be:
- Central–induced centrally in the primary lymphoid organs e.g. thymus for T-L tolerance and bone marrow for B-L tolerance.
- Peripheral–Tolerance in mature B & T-cells.
Owen – 1945 – A veterinary surgeon gave the concept that dizygotic twin sharing blood supply in-utro, later on, tolerate their blood.
Medawar – 1960 – He did experiment on the above hypothesis and introduced antigen in-utro and later on this animal was tolerant of the same antigen when introduced in-utro. He got the Nobel Prize.
Self Immunologic Tolerance
The following are the different explanations and theories for the development of self Immunologic Tolerance.
1. Burnet Clonal Deletion Theory: It is believed that self-antigen reacting B & T-L clones are deleted from the circulation e.g. during the development stages of lymphoid tissue.
This process takes place in the thymus gland.
The same process takes place for B –Lymphocytes. That self Antigen bearing B-cells are deleted by apoptosis in the bone marrow.
There was an objection to clonal deletion theory because later on self-antigen reacting clones of lymphocytes are present in our circulation. This theory was modified that there is clonal anergy.
2. Clonal Anergy:- This is prolonged irreversible functional inactivation of lymphocytes. This is also called clonal purging or clonal silence. Clonal abortion or obligatory paralysis.
Ag–Specific T – L (CD4+) requires two signals:
- Recognition of Ag-peptide with MHC-II.
The second co-stimulating signal provided by APC–TL associated molecule, CD28 must bind to its ligand B7 on APC.
3. B-L also has clonal anergy (B-lymphocyte Tolerance):-
B-lymphocytes during maturation, Ag-receptor (IgM) after self-Ag recognition are endocytosed and Ag-receptor (IgM) is not expressed.
4. Peripheral Suppression by Ts (CD8+) Cells
Ts(CD8+) suppress the immune response by producing cytokines. These are:
TGFb1 – It down-regulates many immune responses. Directly suppress:
- Th cells.
- B- lymphocyte.
- Prevents autoimmune response.
5. Tolerance at Adult Age (Acquired or Peripheral Tolerance):–
B and T lymphocytes can be made tolerant by giving antigens in various doses.
The (CD4+) cells are made tolerant by giving antigen in smaller doses while B-L are made tolerant by giving antigen in larger doses.
So peripheral T-L suppression may be due to:
- Low antigen concentration.
- APC, presenting cell is incapable of a second co-stimulatory signal.
Regulatory Ts cell suppresses the auto reactive T-L.
This is a breakdown of self immunologic tolerance leading to autoimmune diseases. The different mechanisms through which T & B cells tolerance operate lead to an obvious conclusion: Several different pathological processes could break tolerance and lead to autoimmunity.
Tolerance to self-antigen may be broken by:
- Defect in immune regulatory pathways.
- The presence of Ag similarities between pathogenic organisms and self-proteins.
- The provision of new T-cell epitopes to bypass tolerant T-cells.
- The release of “hidden” self-antigen.
- The so-called “aberrant” expression of the MHC class II molecule.
- The influence of cytokines.
- Circumstantial evidence of familial tendency.
- Lymphocytic infiltrate.
- Clinical improvement with immunosuppressive therapy.
Criteria for Autoimmune Diseases
- Presence of autoimmune disease.
- Clinical or experimental evidence of the disease and also this is not due to tissue damage e.g. when administer thyroglobulin will produce thyroiditis.
- Absence of any other evidence of disease.
It has been discussed in various books of immunology in different ways. In this book, I am trying to discuss in such away that it may be easy to reproduce and have a basic concept of mechanism.
1.The basic mechanism may be:
- Evasion of the normal tolerance to self-antigen.
- Hidden antigen (sequestered antigen).
- Alteration of antigen by chemical, drugs or infections.
- Breakdown of tolerance mechanism.
- Agents affecting antibody-forming cells e.g. chemicals, drugs, infections.
- Genetically determined lake of efficiency of tolerance e.g. TS activity.
- Stimulation of pre-existing B-L e.g. by infection.
2. Bypass of Th Tolerance
This can take place by modification of molecular structure of antigen or carrier e.g.
- Modification of the molecular structure of potentially auto antigen (Hapten) complexes with new carrier e.g. a-methyldopa complex with e-antigen on RBC and lead to autoimmune hemolytic anemia.
Partial degradation of auto-antigen where there is the exposure of new antigens like degraded collagen, thyroglobulin, and γ-globulin.
3. Cross-reaction (Molecular Mimicry)
Some of the microbes are source of cross-reaction, as like antibody against these antigens may cross-react with self-antigen. e.g. Rheumatic heart disease where antibody against M-protein of streptococci reacts with M-protein of the sarcolemma of cardiac muscle.
In ulcerative colitis–antigen E.coli 014 form antibody which reacts with colon-polysaccharides.
4. Polyclonal Activation of B-Lymphocytes
There may be direct activation of B-L and Th-cells may be bypassed.
This may take place by:
- Exogenous substances–lipopolysaccharides, Nystatin, PPD, and Amphotericin B.
- Endogenous or intrinsic substances.
- Microbes – virus, bacteria and parasites.
- Proteolytic enzyme-like trypsin.
- Viruses are an important cause of polyclonal activation of B-lymphocytes, they can lead to Bypass of Th-cell.
- Direct stimulation of B-L.
- Loss of Ts.
The B-lymphocytes activation may be due to:
- Genetic abnormality.
- Intrinsic B-cell abnormality.
- Ts-function loss.
5. Idiotype-Bypass Mechanism
It is postulated that idiotype and anti-idiotype network regulate immune response and this may inhibit or activate the response.
One of the examples is Grave’s disease where auto-antibody against TSH-receptor stimulates the thyroid gland.
6. Imbalance of Ts-Th Function
Imbalance of Ts – Th cells is seen with increasing age. In SLE it is found that there is over activity of the Helper cells.
7. The emergence of Sequestered Antigens
There are some auto antigens, which are not exposed to the immune system during developmental stages. When later on these are exposed there is autoantibodies formation e.g. spermatozoa, thyroglobulin, and eye lens.
In 1956–Dressler described autoantibodies formation after myocardial infarction where autoantibody forms against cardiac myocytes because of injury to these muscles. Here the function of the auto antibody is to clear the damage tissue and recycle the effected protein.
Another mechanism is that virus may damage the tissue and expose the intracellular proteins. These autoantigens may incite an immune response.
The last possibility is that appearance of a small number of hidden autoantigens to which peripheral tolerance exists may be sufficient to break it, since tolerance is dependent on the concentration of the antigens.
8. Thymic Defects
The intact thymus gland plays an important role in immunologic stability. Because patient with thymectomy is more prone to develop autoimmune diseases.
9. Defects in Macrophages
As one knows that macrophagic cells are needed for the processing of antigen and their presentation to immune cells. So any defect or abnormality of macrophagic cells may lead to autoimmune diseases.
10. Genetic Factors (Role of HLA)
There are reports of familial clustering of autoimmune diseases. There is a linkage of autoimmune diseases with MHC-II molecule e.g.
|HLA typing||Disease||Risk %|
|DR2 and DR3||Juvenile diabetes||32|
There is a famous history of autoimmune diseases in a family. Where the mother has myxedema and all 6 children show evidence of autoimmune disease or autoantibody.
Cytokines are soluble factors they affect both locally and systemically on cells of the immune system. These cytokines also play some role in development of autoimmune disease e.g.
L-2 is the T-lymphocyte growth and differentiation factor used therapeutically in some solid organs. Tumors to enhance immune-mediated anti-tumors responses. During such IL-2 treatment, an inflammatory lesion with lymphocytic infiltration has been seen in several organs, including myocardium, skin, liver, and thyroiditis like Hashimoto’s which may progress to hypothyroidism in 10% of the cases.
IFN-α therapy: This is used to treat and clear hepatitis C virus infection. These patients may develop type-I diabetes with islets antibody and insulin autoantibody as evidence of autoimmune disease.
- Autoimmune diseases usually arise spontaneously.
- Infection plays a critical role in this process.
- Susceptibility to autoimmune disease is controlled by the environment and genetic factors (especially MHC gene).
Therapy of Autoimmune Diseases
Autoimmune diseases may be treated by various modalities like:
- Replacement therapy for loss of endocrine secretions (insulin, thyroxin).
- “Blanket” suppression of the immune system by giving corticosteroids. This effect on all components of the immune system e.g. interferes in cell activation and migration.
- Cyclosporine A and FK506-inhibit early events in T-cell activation. These inhibit cell-mediated immune response more selectively. These drugs have been used in clinical trials for the treatment of type I diabetes and rheumatoid arthritis.
- Monoclonal antibodies. This will block cell to cell interaction or neutralize positive signals such as cytokines.
Now we will discuss some of the autoimmune diseases. These are also called as Rheumatic diseases or connective tissue or collagen diseases.
Rheumatic denotes the migratory nature of the pain (Greek word) whiles the term connective tissue or collagen indicates the components typically affected.
Also, clinical manifestations center around the joints and muscles, but other systems are involved in differing degrees in different diseases.