By Dr.Shnyar Hamid Qadir Autoimmune diseases By Dr.Shnyar Hamid Qadir

Autoimmune diseases Autoimmunity: is inappropriate response of the immune system, directing humoral and/or T-cell-mediated immune activity against self components. Such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE, or lupus) and certain types of diabetes.

Autoimmune diseases Autoimmune reactions can cause serious damage to cells and organs, sometimes with fatal consequences. In some cases the damage to self cells or organs is caused by antibodies; in other cases, T cells. Autoimmunity results from some failure of the host’s immune system to distinguish self from nonself, causing destruction of self cells and organs.

Self tolerance This process and the mechanisms that control it are collectively termed tolerance, or self-tolerance. 1.central tolerance In the first step of this process, a phenomenon termed central tolerance deletes T- or B-cell clones before the cells are allowed to mature if they possess receptors that recognize self antigens with high affinity

Self tolerance Central tolerance occurs in the primary lymphoid organs; the bone marrow for B cells and the thymus for T cells Because central tolerance is not perfect and some self- reactive lymphocytes find their way into the periphery and secondary lymphoid tissues, additional safeguards limit their activity. these backup precautions include peripheral tolerance

Self tolerance 2.peripheral tolerance: which renders some self-reactive lymphocytes in secondary lymphoid tissues inactive and generates others that actively inhibit immune responses against self. The possibility of damage from self-reactive lymphocytes is further limited by the life span of activated lymphocytes, which is regulated by programs that induce cell death (apoptosis) following receipt of specific signals.

AUTOIMMUNITY Autoimmune disease is caused by failure of the tolerance processes to protect the host from the action of self- reactive lymphocytes. These diseases result from the destruction of self proteins, cells, and organs by: auto-antibodies or self-reactive T cells.

AUTOIMMUNITY Autoimmune disease is estimated to affect between 3% and 8% of individuals in the industrialized world. These diseases are often categorized as either organ- specific or systemic, depending on whether they affect a single organ or multiple systems in the body.

Disease Self antigen/Target gene   Immune effector Addison’s disease Adrenal cells Auto-antibodies Autoimmune hemolytic anemia RBC membrane proteins Graves’ disease Thyroid-stimulating hormone receptor Hashimoto’s thyroiditis Thyroid proteins and cells TH1 cells, Auto-antibodies Type 1 diabetes mellitus Pancreatic beta cells Poststreptococcal glomerulonephritis Kidney Antigen-antibody complexes Multiple sclerosis Brain or white matter TH1 cells and TC cells, auto-antibodies Rheumatoid arthritis Connective tissue, IgG Autoantibodies, immune complexes Systemic lupus erythematosus (SLE) DNA, nuclear protein, RBC and platelet Auto-antibodies, immune complexes

Some Autoimmune Diseases Target Specific Organs Autoimmune diseases are caused by immune stimulatory lymphocytes or antibodies that recognize self components, resulting in cellular lysis and/or an inflammatory response in the affected organ. Gradually, the damaged cellular structure is replaced by connective tissue (fibrosis), and the function of the organ declines.

In an organ-specific autoimmune disease, the immune response is usually directed to a target antigen unique to a single organ or gland The manifestations are largely limited to that organ. The cells of the target organs may be damaged directly by humoral or cell- mediated effector mechanisms. Alternatively, anti-self anti-bodies may overstimulate or block the normal function of the target organ.

1.Hashimoto’s Thyroiditis This disease is much more common in women, Often striking in middle-age An individual produces auto- antibodies and sensitized TH1 cells specific for thyroid antigens. Antibodies are formed to a number of thyroid proteins, including thyroglobulin and thyroid peroxidase, both of which are involved in the uptake of iodine.

1.Hashimoto’s Thyroiditis Binding of the auto-antibodies to these proteins interferes with iodine uptake, leading to decreased thyroid function and hypothyroidism (decreased production of thyroid hormones). The resulting delayed-type hypersensitivity (DTH) response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers. The ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to hypothyroidism.

2. Type 1 Diabetes Mellitus Also called insulin-dependent diabetes Roughly double the incidence observed just 20 years ago. It is seen mostly in youth under the age of 14 and is less common than Type 2, or non-insulin dependent diabetes mellitus. T1DM is caused by an autoimmune attack against insulin- producing cells (beta cells) scattered throughout the pancreas, which results in decreased production of insulin and consequently increased levels of blood glucose.

2. Type 1 Diabetes Mellitus The attack begins with cytotoxic T lymphocyte (CTL) infiltration and activation of macrophages, frequently referred to as insulitis followed by cytokine release and the production of auto- antibodies, which leads to a cell-mediated DTH response and subsequent beta-cell destruction Auto- antibodies specific for beta cells may contribute to cell destruction by facilitating either antibody-mediated complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC).

Treatment The most common therapy for T1DM is daily administration of insulin. Unfortunately, diabetes can remain undetected for many years, allowing irreparable loss of pancreatic tissue to occur before treatment begins.

Some autoimmune diseases are systemic In systemic autoimmune diseases, the immune response is directed toward a broad range of target antigens and involves a number of organs and tissues.

1.Systemic Lupus Erythematosus systemic lupus erythematosus (SLE) is the best examples of a systemic autoimmune disease Like several of the other autoimmune syndromes, this disease is more common in women, with approximately a 9:1 ratio Onset of symptoms typically appears between 20 and 40 years of age

1.Systemic Lupus Erythematosus Affected individuals may produce auto-antibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors. Signs and symptoms include fever, weakness, arthritis, skin rashes, and kidney dysfunction.

Auto-antibodies specific for RBCs and platelets can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively. Immune complexes of auto-antibodies deposited along the walls of small blood vessels, a type III hypersensitivity reaction develops. The complexes activate the complement system and generate membrane-attack complexes and complement fragments that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis, which can lead to widespread tissue damage .

Figure: characteristic “butter fly” rash over the cheeks of a woman with systemic lupus erythematosus.

2.Multiple Sclerosis Multiple sclerosis (MS) is the most common cause of neurologic disability associated with disease in Western countries. MS occurs in women two to three times more frequently than men. like SLE, frequently develops during (approximately 20– 40 years) of age.

2.Multiple Sclerosis Individuals with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers in the brain and spinal cord. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions, ranging from numbness in the limbs to paralysis or loss of vision.

2.Multiple Sclerosis The cause of MS is not well understood. Infection by certain viruses, such as Epstein-Barr virus (EBV), may predispose a person to MS. Some viruses can cause demyelinating diseases, but the data linking viruses to MS are not definitive. Genetic influences are also important.

Environmental Factors Favoring the Development of Autoimmune Disease

As mentioned earlier, some autoimmune syndromes are more common in certain geographic locations or in particular climates. This suggests a link between environmental exposures (some of which may be microbial) or lifestyle factors, such as diet, in the development of autoimmune disease.

Infections may also influence the induction of autoimmunity. 1.For example, tissue pathology following infection may result in the release of sequestered self antigens that are presented in a way that fosters immune activation rather than tolerance induction. 2.Likewise, the molecular structures of certain microbes may share chemical features with self components, resulting in the activation of immune cells with cross-reactive potential.

a number of viruses and bacteria possess antigenic determinants that are similar or even identical to normal host-cell components, led to a hypothesis known as molecular mimicry. For instance, rheumatic fever, a disease caused by autoimmune destruction of heart muscle cells, can develop after a Group A Streptococcus infection. In this case, antibodies to streptococcal antigens have been shown to cross-react with the heart muscle proteins, resulting in immune complex deposition and complement activation, a type II hypersensitivity reaction

Another issue is the sex difference in autoimmune susceptibility, with diseases such as Hashimoto’s thyroiditis, SLE, MS, and RA preferentially affecting women. Factors that may account for this, such as hormonal differences between the sexes and the potential effects of fetal cells in the maternal circulation following pregnancy.

TREATMENT of autoimmune diseases

TREATMENT Ideally, treatment for autoimmune diseases should reduce only the autoimmune response, leaving the rest of the immune system intact. The current therapies to treat autoimmune disease fall into two categories: broad spectrum immunosuppressive treatments and more recent mechanism- or cell-type specific strategies

1.Broad-Spectrum Therapies Most first-generation therapies for autoimmune diseases are not cures but merely palliatives, reducing symptoms to provide the patient with an acceptable quality of life.

1.Broad-Spectrum Therapies Immunosuppressive treatments (e.g., corticosteroids, azathioprine, and cyclophosphamide) are: strong anti-inflammatory drugs Suppress lymphocytes by inhibiting their proliferation or by killing these rapidly dividing cells. Side effects of these drugs include general cytotoxicity, an increased risk of uncontrolled infection, and the development of cancer.

2.Strategies That Target Specific Cell Types (Rituximab) depletes a subset of B cells and provides short-term benefit for RA.

3.Strategies That Interfere with Costimulation Abatacept: Approved for the treatment of RA Has also been studied with limited success in patients with MS, T1DM, SLE, and inflammatory bowel disease. Is drug blocks CD80/86 on APCs from engaging with CD28 on T cells.

Transplantation

Transplantation Refers to the act of transferring cells, tissues, or organs From one site to another—typically from one individual to another. Transfers between two sites on the same individual (e.g., skin) or between identical twins, although not free of complication, are more likely to survive. Many diseases can be cured by implantation of a healthy organ, tissue, or cells (a graft ).

The degree and type of immune response to a transplant varies with the type and source of the grafted tissue. The following terms denote different types of transplants: 1. Autograft: is self tissue transferred from one body site to another in the same individual. Examples include transferring healthy skin to a burned area in burn patients 2. Isograft: is tissue transferred between genetically identical individuals. is occurs in inbred strains of mice or identical human twins, when the donor and recipient are syngeneic.

3. Allograft: is tissue transferred between genetically different members of the same species. In mice this means transferring tissue from one strain to another, and in humans this occurs in transplants in which the donor and recipient are not genetically identical (the majority of cases). 4. Xenograft: is tissue transferred between different species. Because of significant shortages of donated organs, raising animals for the specific purpose of serving as organ donors for humans is under serious consideration.

Autografts and isografts are usually accepted, owing to the genetic identity between donor and recipient. Allograft is genetically dissimilar to the host and therefore expresses unique antigens, it is often recognized as foreign by the immune system and is therefore rejected. Obviously, xenografts exhibit the greatest genetic and antigenic disparity, engendering a vigorous graft rejection response.

Graft Rejection The immune response to tissue antigens encoded within the major histocompatibility complex is the strongest force in rejection. Role of Blood Group and MHC Antigens in Graft Tolerance The most intense graft rejection reactions are due to differences between donor and recipient in ABO blood-group and MHC antigens. The blood-group antigens are expressed on RBCs, requiring the donor and recipient to first be screened for ABO compatibility. If the recipient carries antibodies to any of these antigens, the transplanted tissue will induce rapid antibody-mediated lysis of the incompatible donor cells. For this reason, most transplants are conducted between individuals with a matching ABO blood group.

Next, the MHC compatibility between potential donors and a recipient is determined. The first choice is usually parents or first-order siblings . Molecular assays using sequence-specific primers to establish which HLA alleles are expressed by the recipient and potential donors (called tissue typing) has become more common in recent years, especially in bone marrow transplantation.

The process of graft rejection can be divided into a sensitization stage, in which T cells are stimulated, and an effector stage, in which they attack the graft. A variety of mechanisms participate in the effector stage of allograft rejection. The most common are cell- mediated reactions; less common mechanisms are antibody-mediated complement lysis and destruction by ADCC. The hallmark of graft rejection involving cell-mediated reactions is an influx of immune cells into the graft . Among these are T cells, especially CD4 , and APCs, often macrophages. Histologically, the infiltration in many cases resembles that seen during a DTH response, in which cytokines produced by T cells promote inflammatory cell infiltration

Immunosuppressive Therapy Allogeneic transplantation always requires some degree of immunosuppression if the transplant is to survive. Most immunosuppressive treatments are nonspecific, resulting in generalized suppression of responses to all antigens, not just those of the allograft . This places the recipient at increased risk of infection and cancer. In fact, infection is the most common cause of transplant-related death. Total lymphoid x-irradiation are also used

monoclonal antibodies Experimental approaches using monoclonal antibodies offer the possibility of more specific immunosuppression. These antibodies may act by: Depleting certain populations of reactive cells Blocking TCR engagement or interfering with costimulation Interfering with specific cytokine signaling Example: Rituximab