Immunity Disorders: Autoimmune Diseases

Immunodeficiency

Immunodeficiency occurs when the immune system cannot appropriately respond to infections.

Learning Objectives

Explain the problems associated with immunodeficiency

Key Takeaways

Key Points

  • If a pathogen is allowed to proliferate to certain levels, the immune system can become overwhelmed; immunodeficiency occurs when the immune system fails to respond sufficiently to a pathogen.
  • Immunodeficiency can be caused by many factors, including certain pathogens, malnutrition, chemical exposure, radiation exposure, or even extreme stress.
  • HIV is a virus that causes immunodeficiency by infecting helper T cells, causing cytotoxic T cells to destroy them.

Key Terms

  • phagocyte: a cell of the immune system, such as a neutrophil, macrophage or dendritic cell, that engulfs and destroys viruses, bacteria, and waste materials
  • lysis: the disintegration or destruction of cells
  • immunodeficiency: a depletion in the body’s natural immune system, or in some component of it

Immunodeficiency

Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold to replicate or proliferate to high enough levels that the immune system becomes overwhelmed, leading to immunodeficiency; it may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or, possibly, by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes, elevating an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.

HIV/AIDS

Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system. The person has a high probability of becoming infected, including from opportunistic infections and tumors that do not usually affect people who have working immune systems.

image

Image of HIV: scanning electron micrograph of HIV-1 budding (in green, color added) from cultured lymphocyte: Multiple round bumps on cell surface represent sites of assembly and budding of HIV. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.

After the virus enters the body, there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood. This response is accompanied by a marked drop in the number of circulating CD4+ T cells, cells that are or will become helper T cells. The acute viremia, or spreading of the virus, is almost invariably associated with activation of CD8+ T cells (which kill HIV-infected cells) and, subsequently, with antibody production. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts recover.

Ultimately, HIV causes AIDS by depleting CD4+ T cells (helper T cells). This weakens the immune system, allowing opportunistic infections. T cells are essential to the immune response; without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4+ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4+ T cell depletion, although apoptosis (programmed cell death) may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4+ T cell numbers.

The Roles of Genetics and Gender in Autoimmune Disease

Autoimmunity is the failure of an organism in recognizing “self” which results in an immune response against its own cells and tissues.

Learning Objectives

Define autoimmunity and explain how it gives rise to autoimmune disease

Key Takeaways

Key Points

  • Autoimmune diseases are very often treated with steroids which will dampen the immune response.
  • Certain individuals are genetically susceptible to developing autoimmune diseases and susceptibility is linked to immunoglobulin, T-cell receptor, and MHC complex genes.
  • Women are more likely than men to develop an autoimmune disease, but the severity of the disease is more accentuated in men.

Key Terms

  • autoimmunity: The condition where one’s immune system attacks one’s own tissues, i.e., an autoimmune disorder.
  • alloimmunity: Immunity, obtained from another, against one’s own cells.

Autoimmunity is the failure of an organism in recognizing its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Autoimmunity is often caused by a lack of germ development of a target body and as such the immune response acts against its own cells and tissues. Prominent examples include Coeliac disease, diabetes mellitus type 1 (IDDM), Sarcoidosis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, Churg-Strauss Syndrome, Hashimoto’s thyroiditis, Graves’ disease, idiopathic thrombocytopenic purpura, Addison’s Disease, rheumatoid arthritis (RA), and allergies.

Autoimmune diseases are very often treated with steroids. The misconception that an individual’s immune system is totally incapable of recognizing self antigens is not new. Paul Ehrlich, at the beginning of the 20th century, proposed the concept of horror autotoxicus, wherein a ‘normal’ body does not mount an immune response against its own tissues. Therefore, any autoimmune response was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed ‘natural autoimmunity’), normally prevented from causing disease by the phenomenon of immunological tolerance to self-antigens.

Autoimmunity should not be confused with alloimmunity. While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. First, low-level autoimmunity might aid in the recognition of neoplastic cells by CD8+ T cells, and thus reduce the incidence of cancer. Second, autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response (i.e., when there are few pathogens present).

Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. However, genetically predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to immunoglobulins, T-cell receptors, and the major histocompatibility complexes (MHC). Immunoglobulins and T-cell receptors are involved in the recognition of antigens and they are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity. Scientists such as H. McDevitt, G. Nepom, J. Bell, and J. Todd have also provided strong evidence to suggest that certain MHC class II allotypes are strongly correlated with disease. For example:

1. HLA DR2 is strongly positively correlated with Systemic Lupus Erythematosus, narcolepsy and multiple sclerosis, and negatively correlated with DM Type 1.

image

MHC Class II, DR: HLA-DR is a MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR and its ligand, a peptide of 9 amino acids in length or longer, constitutes a ligand for the T-cell receptor (TCR).

2. HLA DR3 is correlated strongly with Sjögren’s syndrome, myasthenia gravis, SLE, and DM Type 1.

3. HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1 diabetes mellitus, and pemphigus vulgaris.

Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and ankylosing spondylitis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease. The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease (Linda Wicker’s extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin’s linkage analysis of susceptibility to SLE).

A person’s sex also seems to have some role in the development of autoimmunity, classifying most autoimmune diseases as sex-related diseases. Nearly 75% of the more than 23.5 million Americans who suffer from autoimmune disease are women, although it is less-frequently acknowledged that millions of men also suffer from these diseases. However, autoimmune diseases that develop in men tend to be more severe. A few autoimmune diseases that men are just as or more likely to develop as women, include: ankylosing spondylitis, type 1 diabetes mellitus, Wegener’s granulomatosis, and Crohn’s disease. The reasons for the sex role in autoimmunity are unclear. However, women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity. In addition, involvement of sex steroids is indicated by the fact that many autoimmune diseases tend to fluctuate in accordance with hormonal changes, for example, during pregnancy. Interestingly, a history of pregnancy also appears to leave a persistent increased risk for autoimmune disease. Indeed, it has been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity. This would tip the gender balance in the direction of the female. Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced X chromosome inactivation.

Cytotoxic Autoimmune Reactions

Autoimmunity is a result of the failure of an organism’s immune system to recognize “self”.

Learning Objectives

Define autoimmunity and describe how it can lead to disease

Key Takeaways

Key Points

  • Autoimmunity is often caused by a lack of germ development of a target body and, as such, the immune response acts against its own cells and tissues.
  • Certain individuals are genetically susceptible to developing autoimmune diseases but genetically predisposed individuals do not always develop an autoimmune disease.
  • Three main sets of genes are suspected in many autoimmune diseases: immunoglobulins, T-cell receptors and the major histocompatibility complexes (MHC).
  • Women are more likely to develop an autoimmune disease.

Key Terms

  • alloimmunity: Immunity, obtained from another, against one’s own cells.
  • autoimmunity: The condition where one’s immune system attacks one’s own tissues, i.e., an autoimmune disorder.

Autoimmunity is the failure of an organism in recognizing its own constituent parts as self, creating an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease.

Autoimmunity is often caused by a lack of germ development of a target body and, as such, the immune response acts against its own cells and tissues. Prominent examples include Coeliac disease, diabetes mellitus type 1 (IDDM), Sarcoidosis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, Churg-Strauss Syndrome, Hashimoto’s thyroiditis, Graves’ disease, idiopathic thrombocytopenic purpura, Addison’s Disease, rheumatoid arthritis (RA) and allergies.

Autoimmune diseases are very often treated with steroids. The misconception that an individual’s immune system is totally incapable of recognizing self antigens is not new. Paul Ehrlich, at the beginning of the twentieth century, proposed the concept of horror autotoxicus, wherein a ‘normal’ body does not mount an immune response against its own tissues. Thus, any autoimmune response was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed ‘natural autoimmunity’), normally prevented from causing disease by the phenomenon of immunological tolerance to self-antigens.

Autoimmunity should not be confused with alloimmunity. Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases: immunoglobulins, T-cell receptors and the major histocompatibility complexes (MHC).

Immunoglobulins and the T-cell receptors are involved in the recognition of antigens and they are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity. Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence to suggest that certain MHC class II allotypes are strongly correlated with autoimmunity.

For example:

1. HLA DR2 is strongly positively correlated with Systemic Lupus Erythematosus, narcolepsy and multiple sclerosis, and negatively correlated with DM Type 1.

2. HLA DR3 is correlated strongly with Sjögren’s syndrome, myasthenia gravis, SLE, and DM Type 1.

3. HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1 diabetes mellitus, and pemphigus vulgaris.

Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and ankylosing spondylitis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease. The contributions of genes outside the MHC complex remain the subject of research both in animal models of disease (Linda Wicker’s extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin’s linkage analysis of susceptibility to SLE).

A person’s sex also seems to have some role in the development of autoimmunity, classifying most autoimmune diseases as sex-related diseases. Nearly 75% of the more than 23.5 million Americans who suffer from autoimmune disease are women, although it is less-frequently acknowledged that millions of men also suffer from these diseases.

According to the American Autoimmune Related Diseases Association (AARDA), autoimmune diseases that develop in men tend to be more severe. A few autoimmune diseases that men are just as or more likely to develop as women, include: ankylosing spondylitis, type 1 diabetes mellitus, Wegener’s granulomatosis, Crohn’s disease, Primary sclerosing cholangitis and psoriasis.

The reasons for the sex role in autoimmunity are unclear. Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity. Similarly, involvement of sex steroids is indicated by the fact that many autoimmune diseases tend to fluctuate in accordance with hormonal changes. Interestingly, a history of pregnancy also appears to leave a persistent increased risk for autoimmune disease. Indeed, it has been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity. This would tip the gender balance in the direction of the female.

Another theory suggests the female-high tendency to get autoimmunity is due to an imbalanced X chromosome inactivation. The X-inactivation skew theory, proposed by Princeton University’s Jeff Stewart, has recently been confirmed experimentally in scleroderma and autoimmune thyroiditis.

Immune Complex Autoimmune Reactions

An immune complex is formed from the integral binding of an antibody to a soluble antigen and can function as an epitope.

Learning Objectives

Describe how immune complex autoimmune reactions arise

Key Takeaways

Key Points

  • After an antigen – antibody reaction, the immune complexes can be subject to any of a number of responses including complement deposition, opsonization, phagocytosis, or processing by proteases.
  • Immune complexes may cause disease when they are deposited in organs.
  • The Arthus reaction involves the in situ formation of antigen/antibody complexes after the intradermal injection of an antigen (as seen in passive immunity).

Key Terms

  • epitope: That part of a biomolecule (such as a protein) that is the target of an immune response.
  • immune complex: An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex.

An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases. Red blood cells carrying CR1-receptors on their surface may bind C3b-decorated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return back to the general circulation. Immune complexes may cause disease when they are deposited in organs, e.g. in certain forms of vasculitis. This is the third form of hypersensitivity in the Gell-Coombs classification, called Type III hypersensitivity. Immune complex deposition is a prominent feature of several autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, rheumatoid arthritis, scleroderma, and Sjögren’s syndrome.

image

Immune Complex Diseases: An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex.

In immunology, the Arthus reaction is a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated. They involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli. The Arthus reaction involves the in situformation of antigen/antibody complexes after the intradermal injection of an antigen (as seen in passive immunity). If the animal/patient was previously sensitized (has circulating antibody), an Arthus reaction occurs. Typical of most mechanisms of the type III hypersensitivity, Arthus manifests as local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels. Activation of complement primarily results in cleavage of soluble complement proteins forming C5a and C3a, which activate recruitment of PMNs and local mast cell degranulation (requiring the binding of the immune complex onto FcγRIII), resulting in an inflammatory response. Further aggregation of immune complex-related processes induces a local fibrinoid necrosis with ischemia-aggravating thrombosis in the tissue vessel walls. The end result is a localized area of redness and induration that typically lasts a day or so. Arthus reactions have been infrequently reported after vaccination against diphtheria and tetanus.

Cell-Mediated Autoimmune Reactions

Cell-mediated autoimmunity can happen by several mechanisms involving cells of the immune system and their receptors.

Learning Objectives

Define cell-mediated autoimmunity and describe the mechanisms that are thought to operate in the pathogenesis of autoimmune disease

Key Takeaways

Key Points

  • Superantigens can bypass the T-cell requirement for B cell activation.
  • In some instances such as celiac disease, B cells can be activated to produce antibodies to epitope A by T cells activated by epitope B.
  • Autoreactive B cells in spontaneous autoimmunity survive due to subversion both of the T cell help pathway and of the feedback signal through B cell receptor, leading to loss of the negative signals responsible for B cell self- tolerance without necessarily requiring loss of T cell self-tolerance.
  • DQ therefore is involved in recognizing common self- antigens and presenting those antigens to the immune system in order to develop tolerance from a very young age.

Key Terms

  • autoimmunity: The condition where one’s immune system attacks one’s own tissues, i.e., an autoimmune disorder.
  • tolerance: The process by which the immune system does not attack an antigen

Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. Four of the important mechanisms are described below.

T Cell Bypass

A normal immune system requires the activation of B cells by T cells before the former can produce antibodies in large quantities. This requirement of a T cell can be bypassed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B cells, or even of T cells, by directly binding to the β-subunit of T cell receptors in a non-specific fashion.

T Cell to B Cell Discordance

A normal immune response is assumed to involve B and T cell responses to the same antigen, where B cells recognize conformations on the surface of a molecule for B cells, and T cells recognize pre-processed peptide fragments of proteins for T cells. However, there is no evidence that this response is required. All that is required is that a B cell that recognizes antigen X endocytoses processes a protein Y (normally =X) and presents it to a T cell. Roosnek and Lanzavecchia showed that B cells recognizing IgGFc could get help from any T cell that responds to an antigen co-endocytosed with IgG by the B cell as part of an immune complex. In coeliac disease it seems likely that B cells that recognize transglutamine tissue are helped by T cells that recognize gliadin.

Aberrant B Cell Receptor-Mediated Feedback

A feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response (for example DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin receptor(PNAR)). This fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent B cells through membrane bound ligands. These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21 (which binds complement C3d), Toll-like receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR. More indirect aberrant activation of B cells can also be envisaged with autoantibodies to acetyl choline receptor (on thymic myoid cells) and hormone binding proteins. Together with the concept of T cell-B cell discordance, this idea forms the basis of the hypothesis of self-perpetuating autoreactive B cells. Autoreactive B cells in spontaneous autoimmunity are seen as surviving because of subversion both of the T cell help pathway and of the feedback signal through the B cell receptor. This reaction thereby overcomes the negative signals responsible for B cell self-tolerance without necessarily requiring loss of T cell self-tolerance.

Dendritic Cell Apoptosis

image

MHC Class II, DQ: HLA-DQ (DQ) is a cell surface receptor type protein found on antigen presenting cells (APC). DQ is an alpha-beta heterodimer of the MHC class II type.

Immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.

HLA-DQ (DQ) is a cell surface receptor type protein found on antigen presenting cells. DQ is an α heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus four DQ isoforms.

DQ isoforms can bind to and present foreign and self antigens to T-cells. In this process T-cells are stimulated to grow and can signal B-cells to produce antibodies. DQ therefore is involved in recognizing common self-antigens and presenting those antigens to the immune system in order to develop tolerance from a very young age. When tolerance to self proteins is lost, DQ may become involved in autoimmune disease. Two autoimmune diseases in which HLA-DQ is involved are celiac disease and diabetes mellitus type 1. DQ is one of several antigens involved in rejection of organ transplants. As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus host disease when lymphoid tissues are transplanted between people.