Is the Autoimmune Response Antigen-Dependent?

complex structural elements. For example, in patients with systemic lupus erythematosus and in

NZB/NZW mouse DNA antibodies include several different types.

It has been shown that in NZB mice, the parental mice of NZB/NZW, the first antibody production is only in a subset of B cells that carry the CD5 marker, a common T-cell marker. This is a matter of debate. IgG antibodies, the most common class of antibodies in all severe autoimmune diseases, cannot be produced by CD5+ B cells, which produce only IgM. It is also possible that CD5+ B cells are precursors to IgG-producing cells, but this has not been established.

A significant proportion of CD5+ B cells also appear to be involved in the production of IgM rheumatoid factor, since it has been shown that virtually all B cells in patients with chronic lymphocytic leukemia are CD5-positive and that the majority of them produce IgM rheumatoid factor. It should be remembered that IgM rheumatoid factor, whether produced by normal or tumor cells, is encoded by germline Ig genes, meaning that it is not somatically mutated. This is not due to lack of stimulation, but because normal B cells are known to produce rheumatoid factor, and this production increases during infection. Taken together, these observations suggest that the body's natural regulator of the autoimmune response is always to prevent mutations that would otherwise produce abnormally large amounts of rheumatoid factor. However, in rheumatoid arthritis, the regulation is lost, rheumatoid factor is produced in large quantities with polyclonal properties and IgG rheumatoid factor appears.

11.1.3. Is the autoimmune response antigen dependent?

It is clear that the autoimmune response requires many of the same factors as the normal immune response and is controlled by many of the same rules as the normal immune response. It is therefore conceivable that an autoimmune response can be generated in response to a specific antigenic stimulus. In addition, autoimmune disease can be triggered by specific infections such as streptococcal pharyngitis, intestinal infections caused by Shigella, Salmonella, Yersinia or Campylobacter.

Nonspecific stimuli can also lead to autoimmune responses, as in the case of B cells activated by allogeneic T cells in a graft-versus-host reaction. In the NZB/NZW mouse, Steinberg et al. suggested that the initial T cell autoimmune response may be nonspecific. However, in both human and NZB/NZW mouse graft-versus-host reactions, autoimmune responses require very strict conditions. In mice

NZB/NZW, at the time of disease progression, Steinberg et al. found that the disease had become antigen-directed because of an autoimmune response that had occurred following lymphocyte infusion.

11.2. Evidence for the pathogenic nature of autoimmune reactions: Experimental autoimmune reactions

It is believed that if autoimmune reactions can cause certain pathological lesions in humans, then we can also create a model of autoimmune lesions in experimental animals. Indeed, it has been possible to stimulate the creation of organ-specific autoimmune diseases in animals by injecting antigens with complete Freud's adjuvant. For example, thyroglobulin can cause thyroiditis, and myelin basic protein can cause experimental encephalomyelitis. This organ specificity is not at all disputed because the antigens have been found at the sites of damage. In the case of animals injected with thyroglobulin, not only antithyroid antibodies appear, but also the gland is infiltrated by mononuclear cells, and the structure of the gland follicles is destroyed under the influence of autoantigens. Although not similar to Hashimoto's disease, thyroiditis here also has important similarities with the disease in humans.

Strain susceptibility to autoimmune disease

Whether we can induce autoimmune disease depends on the animal strain used. For example, it has been shown that the susceptibility of mice to myelin basic protein-induced encephalomyelitis depends on certain genetic loci, the most important of which are the genes of the major histocompatibility complex (MHC) class II. Once a suitable susceptible animal strain is obtained, it is also possible to induce passive disease by transferring sensitized T cells (e.g. sensitized to myelin basic protein) to another animal. These cells are phenotypically CD4+ cells, based on this property, anti-CD4+ antibodies have been used to control the disease and have obtained good results in experimental animals. Similar results have been obtained with experimental autoallergic thyroiditis caused by thyroglobulin. These results demonstrate that autoreactive T cells operate under very strict MHC conditions, and that this condition is important in generating experimental disease states.

Antibody mediated diseases

In some experimental models, antibodies rather than T cells are the primary causative agents. For example, anti-acetylcholine receptor antibodies cause the muscle weakness characteristic of experimental myasthenia gravis; glomerular basement membrane antibodies found in experimental Goodpasture's disease can be produced by injecting the animal with antigen (glomerular basement membrane extract) along with Freud's adjuvant.

spontaneous autoimmune diseases

We can learn a lot by studying naturally occurring autoimmune diseases in animals.

Thyroid disease in Obese chickens : In Obese chickens, naturally occurring antithyroid antibodies were found, and the thyroid gland gradually degenerated with chronic inflammatory lesions. The serum of these animals contained antithyroglobulin antibodies. In addition, about 15% of the serum samples reacted with the proventriculus (stomach) of normal chickens. This antibody is similar to the anti-human gastric parietal cell antibody of patients with pernicious anemia. Thus, the animal model here is considered equivalent to spontaneous autoimmune thyroid disease in humans in terms of glandular damage, production of autoantibodies against various components of the thyroid gland, and an autoimmune reaction to the stomach. If we change the immune status of the animal, the disease manifestations also change: when we remove the Fabricius gland, the thyroiditis reaction is reduced, which proves that antibodies play an important role in the etiology of the disease. Conversely, if the thymus gland is removed at birth, the disease seems to be more severe.

Systemic lupus erythematosus in mice : Another experimental model was developed in the F1 hybrid generation of NZB and NZW mice. These hybrid mice showed spontaneous systemic lupus erythematosus with immune complex glomerulonephritis and the appearance of various autoantibodies in the blood, the most important of which were antinuclear antibodies with various specificities. In these animals, immunosuppressants such as cyclophosphamide, cyclosporin A, etc. were effective in inhibiting the onset of the disease and prolonging the survival of the animals.

11.3. Arrangement of common autoimmune diseases in humans

Diseases involving autoimmune phenomena are often grouped into two categories, commonly referred to as the autoimmune spectrum (Figure 11.1). At one end of the spectrum are Hashimoto's thyroiditis and a number of diseases in which autoantibodies and damage occur only in one organ of the body and are called organ-specific autoimmune diseases.

organ-specific autoimmune diseases. At the other end of the spectrum, systemic lupus erythematosus is considered a typical systemic autoimmune disease. In lupus and diseases at this extreme, autoantibodies react with many types of antigens scattered throughout the body and characteristic damage also occurs in many organs, so they are called non-organ-specific autoimmune diseases.

Common target organs in organ-specific diseases are the thyroid, adrenal glands, stomach, and pancreas; whereas in non-organ-specific diseases including rheumatic diseases, lesions may occur in the skin, kidneys, joints, and muscles.

It is worth noting that at each end of the list of diseases that are placed next to each other, there is often overlap in both clinical and paraclinical symptoms. For example, thyroid antibodies appear with high frequency in patients with pernicious anemia who have gastric autoimmunity. At the same time, these patients have a higher frequency of thyroid autoimmunity than normal people. Similarly, among patients with thyroid autoimmunity, there is an unusually high proportion of people with gastric parietal cell autoantibodies, some of whom also have symptoms of pernicious anemia. In particular, if we consider the group of rheumatic diseases located on the non-organ-specific side, there is a very common overlap between diseases in that group. For example, symptoms of rheumatoid arthritis often occur with symptoms of SLE. Immune complexes between autoantigens and autoantibodies tend to be deposited throughout the body, especially in the kidneys, joints and skin, causing symptoms in these organs in diseases with this immune complex. However, it should be remembered that the farther apart the disease is on both ends, the rarer the overlap, for example, the simultaneous occurrence of thyroiditis and SLE is extremely unusual.

The immunopathological mechanisms in autoimmune diseases vary according to the position of the disease on the list. If the disease is at the organ-specific pole, the most important mechanisms are type II hypersensitivity and cell-mediated immune responses. The specific mechanisms in non-organ-specific diseases are always related to the site of immune complex deposition. We can see the manifestations of organ-specific and non-organ-specific diseases summarized in Table 11.1.

Organ specificity

Nonspecific

agency

 Hashimoto

 Inflammatory edema

 Thyrotoxicosis

 Pernicious anemia

 Autoimmune atrophic gastritis

 Addison's disease

 Early menopause (some cases)

 Male infertility (some cases)

 Myopathy

 Juvenile diabetes

 Goodpasture syndrome

 Pemphigus vulgaris

 Pemphigoid

 Sympathetic inflammation

 Crystalline uveitis with fibrosis

 Autoimmune hemolytic anemia

 Primary idiopathic thrombocytopenia

 Idiopathic leukopenia

 Primary biliary cirrhosis

 Chronic active hepatitis with negative HBs

 Hepatic cirrhosis

 Ulcerative colitis

 Sjogren's syndrome

 Rheumatoid arthritis

 Scleroderma

 Dermatomyositis

 Discoid lupus

 Systemic lupus erythematosus

Figure 11.1. Spectrum of autoimmune diseases

Table 11.1. Organ-specific and non-organ-specific disorders

Organ specificity	Non-organ specific
Antigen	Residing in a certain agency	Everywhere in the body
Damage	Organ antigens are the targets of immune responses.	Immune complex sedimentation all over the body, especially in kidneys, joints and skin
Duplicate	With antibodies and diseases other organ specific	With antibodies and other organ-specific diseases

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11.4. Genetics of autoimmune diseases

The familial nature of autoimmune diseases is well established. This familial nature is largely genetic rather than environmental, and this has been demonstrated by genetic studies of twins, which have investigated the association between autoantibodies and chromosomal abnormalities.

When there is a phenomenon of simultaneous appearance of symptoms of several organ-specific diseases in an individual, the tendency of the appearance of autoimmunity in his family also leans towards organ-specific autoimmunity. At the same time, the genetic control factors will then lean towards the organ that is most affected. It is interesting to note that relatives of people with Hashimoto's disease have a higher frequency of thyroid autoantibodies and higher titers of this autoantibody than other people. The same phenomenon is also seen in pernicious anemia.

Other evidence for the action of genetic factors is the tendency of autoimmune diseases to be associated with HLA specificities. Haplotypes B8 and DR3 appear at high frequencies in organ-specific diseases. In rheumatoid arthritis, previously when only the A and B loci were examined, they were found to be associated with HLA-Dw4 and DR4. Individuals carrying these HLAs tend to be more susceptible to this type of arthritis. In insulin-dependent diabetes, heterozygosity for DR3 and DR4 is very common. This supports the notion that the genetic factors involved in the occurrence of autoimmune diseases are of two types, one type of factors that predispose to the occurrence of autoimmunity and the other type of factors that determine which autoantigens participate in the autoimmune response.

11.5. Etiology

If we find autoantibodies in a disease, there are three possible explanations for the origin of the disease.

1. The autoimmune reaction occurs first and is responsible for producing the characteristic lesions of the disease.

2. The disease occurs first, then the tissue damage caused by the disease leads to

to autoantibody production.

3. There may be a single factor that simultaneously causes both the disease damage and the autoimmune response. (Figure 11.2)

Autoantibodies that appear after injury can be seen in cases such as myocardial autoantibodies that appear after myocardial infarction. However, in most cases, the production of autoantibodies does not arise from the release of autoantigens after a simple injury. It is generally believed that the majority of diseases that have autoantibodies are caused by autoimmune mechanisms.

Autoimmunity

Sick

Other factors

Figure 11.2. Hypothesis of the association between autoimmune disease and autoimmune response

Three possible combinations can occur: (1) The autoimmune response can produce the disease; (2) The disease is responsible for producing the autoimmune response; or (3) A third factor produces both the autoimmune response and the autoimmune disease.

The most direct evidence for the hypothesis that autoimmune reactions cause autoimmune diseases is that we can model them in animals by experimentally inducing autoimmune reactions. Indeed, many autoimmune diseases have been produced in experimental animals by injecting antigens mixed with Freund's adjuvant. For example, injection of thyroglobulin can induce thyroiditis, and injection of myelin basic protein can induce experimental encephalitis. In the case of thyroglobulin injection, not only

Antithyroid antibodies are produced, the thyroid is infiltrated by mononuclear cells, and the glandular architecture is altered. This experimental thyroiditis is generally very similar to human thyroiditis, although not identical to Hashimoto's.

There are animal models of spontaneous autoimmune diseases that are very useful for our research. The first is autoimmune thyroid disease in Obese (OS) roosters. The disease occurs naturally with chronic thyroiditis and the appearance of anti-thyroid antibodies. If we examine the serum of these animals, in addition to thyroglobulin antibodies, there are also stomach antibodies in over 15% of cases. Thus, in the animal, there are two simultaneous autoimmune processes against the thyroid gland and the digestive gland in the stomach, as is often seen in humans. If we change the immune status of the animal, the clinical picture will also change. For example, if the Fabricius gland is removed, the severity of thyroiditis is significantly reduced, proving that the role of autoantibodies in this disease is very important. On the contrary, if we remove the thymus, it plays a role in controlling the development of the disease.

TSH

Thyroid antibodies

TSH receptor

Thyroid cells

Stimulate

Figure 11.3. Autoimmune response

for cell membrane receptors Thyroid cells are stimulated when the TSH receptor binds to TSH. Anti-TSH antibodies in the serum of Graves' patients may produce similar stimulation and cause the cells to

In humans, it is obviously impossible to perform direct experiments, but there is considerable evidence that autoantibodies are an important pathogenic factor. In some diseases, autoantibodies to hormone receptors have been found to stimulate the receptor in a way that mimics the action of hormones (Figure 11.3), thus producing a clinical picture resembling true hyperactivity. Thyrotoxicosis was probably the first known disorder of this type in which antibodies to the TSH receptor were recognized as the cause. At the same time, thyrotoxicosis sometimes occurs in neonates, suggesting that passive transmission of maternal antibodies may also be involved in the disease.

Another example of an autoimmune disease is male infertility, where anti-sperm autoantibodies cause sperm to stick together. And, then, it becomes clear that they have trouble swimming to reach the egg as they normally would.

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