In this article we will discuss about the autoimmune and immunodeficiency disorders.
A fundamental property of the immune system is its ability to recognize the body’s own cells and the antigens present in them as self-antigens. Under normal conditions, the immune system does not attack self-antigens. This ability — tolerance, develops while the immune cells like B-cells and T-cells mature from their precursor cells.
During maturation, the cells which bind to self-antigens (MHC proteins) are eliminated, while a small proportion of the total population of lymphocytes which does not react with self-molecules survive. Thus, tolerance can be defined as immunological unresponsiveness to self-antigens which are present at birth, because the elimination process takes place mainly in the embryonic cells.
Autoimmunity refers to the state when tolerance to self-antigens breaks down and the immune system attacks the self-antigens. When such attack results in damage of tissues and organs of the body through its own immune system, autoimmune diseases develop. Such diseases may arise through production of antibodies which interact with self-antigens, or through activation of T-cells capable of attacking self-cells.
(ii) Causes of Tolerance Failure:
The mechanisms involved in development of autoimmune diseases due to break-down of self- tolerance are not well-understood. Some of the possible causes of tolerance failure are briefly discussed below. One possible mechanism is molecular mimicry.
When a foreign antigen, like a virus or a microbe, possesses antigenic determinants which are identical or closely similar to a self-antigenic determinant, the immune system fails to distinguish them and may cross-react with both the non-self as we’ll as the self-antigen causing destruction of both the pathogen and the self-cells.
An example of such molecular mimicry is the similarity of a protein of hepatitis C virus and a self-protein, both having a more or less similar amino acid sequence. Another example is provided by a common antigenic determinant present in Group A Streptococcus and heart muscle cells. Cross-reactive antibodies produced by the bacterial antigen also react with the self-antigens resulting in damage of heart (rheumatic heart disease).
Another cause of autoimmune response is polyclonal activation of lymphocytes. Some antigens of microbial origin can activate lymphocytes irrespective of their antigenic specificity e.g. the lipopolysaccharides of Gram-negative bacteria and Epstein-Barr virus.
Because these agents provoke immune response to produce many clones of antibody producing B-cells, they are said to be polyclonal and the antibodies show cross-reactivity with self as well as non-self antigens. Such polyclonal activation of B-cells is believed to by-pass the participation of T-helper cells, which is normally required for B-cell activation (T-independent antigens).
Autoimmunity may also result from certain drugs when their molecules act like haptens and are chemically attached to the surface antigens of body cells. This leads to alteration of their antigenic specificity, so that the immune system recognizes those body cells as non-self and attacks them.
An example of such drug-induced autoimmune disease is thrombocytopenia, a condition of abnormally low count of platelets in blood. Drugs, like aspirin, antihistaminic and some antibiotics are among the agents which result in impaired blood-clotting due to reduced platelet (thrombocytes) count.
Still another possibility of origin of autoimmunity is that certain cells and tissues are either anatomically isolated from the immune system in the embryonic stage when tolerance develops, or they are absent at birth. Such cells and tissues (antigens) are recognized by the body’s immune system as non-self.
Normally, these antigens remain isolated from the immune system (sequestered), but infection or trauma may expose them to the action of immune cells and molecules, resulting in autoimmune responses. The examples of such sequestered antigens are the lens tissue of the eye, nerve cells; spermatozoids etc.
(iii) Some Autoimmune Diseases:
This disease is caused by antibody-mediated stimulation of the thyroid gland resulting in enlargement of the gland (goiter) and production of excess of thyroid hormone. The antibodies bind to the receptors of the gland cells which normally function as receptors for the thyroid stimulating hormone (TSH) produced by the pituitary gland. Thus, the TSH-receptor act as antigeri for the antibody and the binding leads to long-standing thyroid stimulation causing Grave’s disease.
It is a cytotoxic autoimmune disease affecting muscles. The disease is mediated by antibodies which bind to the membrane of muscle fibres and combine with receptors that normally accept acetyl choline As a result, the reception of nerve impulses by the muscle fibres is hampered and muscle activity is seriously affected. In an advanced stage, the disease may prove fatal due to arrest of respiration caused by loss of activity of the muscles of diaphragm and chest.
Systemic lupus erythematosus (SLE):
It is considered as an autoimmune disease, because antibodies are formed in one’s own body against the body’s disintegrating leucocytes.
The nucleoproteins of these leucocytes act as auto-antigens. The complexes formed by combination of these auto-antigens and their complimentary antibodies stimulate complement and produce local skin rash on face (butterfly rash), or the complexes may also produce lesions in blood vessels of kidney and heart.
In this crippling autoimmune disease, immune complexes are deposited in the joints producing chronic inflammation, eventually resulting in serious damage of cartilages and bones. The immune complexes, also known as rheumatoid factors are formed by binding of IgM molecules to the Fc-domains of IgG antibodies and complement proteins. As the constituents of rheumatoid factors come from the same person, the disease is considered as an autoimmune one.
Insulin-dependent diabetes mellitus:
This is a cell-mediated autoimmune disease which results in destruction of the insulin-secreting β -cells of pancreas by T-cells. A host of other autoimmune diseases are also known. Among them are Addison’s disease in which adrenocortical cells (ACTH receptors) act as antigen, Hashimoto’s thyroiditis in which the auto-antigen is thyroglobulin, Good pasture’s syndrome in which the basement membrane of kidney and lungs (type of collagen) act as auto-antigen, and other diseases.
(iv) Factors Predisposing Autoimmune Diseases:
The inheritance pattern of human leucocyte antigen (HLA) controlled by the MHC genes is thought to be responsible for relative proneness to autoimmune diseases. Certain autoimmune diseases, like those affecting thyroid gland, are known to occur in genetically related females. Also, mutations in genes controlling activation of lymphocytes and synthesis of complement proteins are considered to have a major role in increasing risk of SLE-like diseases.
Age and sex:
Autoimmune diseases generally appear in aged persons, possibly due to natural decay of the immune system which, due to aging, becomes less efficient in regulation. In general, women have a greater risk for developing autoimmune diseases than men.
For example, SLE and Grave’s diseases occur predominantly in women. The risk factors are respectively 10 and 7 times higher than that of men. The endocrine hormones are considered as important predisposing factors for this differential risk.
This is supported by animal experiments. Removal of ovaries of female mice makes them more resistant to autoimmune diseases, suggesting that the ovarian hormone, oestrogen, plays an important role. Application of the male sex hormone, testosterone, also makes the female mice more resistant to autoimmune diseases, like SLE.
Certain pathogenic agents, like Epstein-Barr virus, streptococci, malarial parasites, mycoplasmas etc. are known to cause specific autoimmune diseases. Some of these agents have antigenic determinants which have close structural similarity to the antigenic determinants of body cells (self-antigens). These microbial antigenic determinants induce formation of antibodies which can also bind to the self-antigens producing autoimmune reactions (molecular mimicry).
For example, the heat- shock proteins of many microorganisms possess a high degree of similarity in amino acid sequences with the corresponding human proteins. As a consequence, the antibodies produced against the microbial heat-shock proteins show cross-reactivity also to human proteins producing autoimmune responses.
The immune system is primarily responsible for protection against infections diseases. This function of the immune system is carried out by its different components, e.g. B-cells produce antibodies responsible for humoral immunity, T-cells are responsible for cell-mediated immunity, as well as for activation of B-cells and macrophages, the complement helps in T-cell function and in attracting phagocytes, etc.
Immune deficiency can affect any one or more of these components of the immune system. As a result, an individual suffering from immunodeficiency falls prey to repeated infections by one or more of the pathogenic agents.
Immunodeficiency can be congenital or acquired:
(i) Congenital Immune Deficiency:
An individual born with a defective immune system suffers from congenital or primary immune deficiency. Such deficiency arises from genetic changes which are inherited. Presumably, mutations in the genes controlling the formation of different components of the immune system account for the origin of the congenital immune deficiencies.
For example, in a disease known as Bruton’s agammaglobulinemia, mature B-cells fail to develop from the pre-B cells in the bone marrow. As a result, a patient suffering from this disease cannot produce immunoglobulin and becomes highly susceptible to infectious diseases, specially those caused by encapsulated cocci, like streptococci, staphylococci and pneumococci. Such susceptibility is probably due to the lack of IgG antibodies which opsonize the capsulated bacteria and facilitate their elimination by phagocytosis. Usually, a child born with such a defect does not survive long, unless specially protected from infectious diseases.
Deficiency in humoral immunity may also arise from defective regulation of T-helper cells which secrete specific cytokines to induce proliferation, activation and transformation of B-cells into plasma cells. Also, different types of T-helper cells, like TH-1 and TH-2 cells, participate in the class switching in antibody formation through specific cytokines. Thus, any mutations in the genes coding for these proteins (cytokines) may have a pronounced effect on their activity and function.
Not only cytokines, but other protein ligands present on B-cells and T-cells which take part in their binding with other effector cells are also liable to modification through mutation. For example, an activated B-cell initially producing IgM switches over to production of IgG by binding a TH-1 cell with the CD40 protein ligand.
The binding induces the TH-1 cell to produce the cytokine, interferon y, which makes the switchover possible. In an immune deficiency disease, known as hyper-IgM syndrome, the affected person contains high concentration of IgM, but little or no IgG. This defect arises from a mutation in the gene coding for CD40 protein of B-cells. As a result, the class-switching from IgM to IgG is blocked.
Just as defects in B-cells and T-helper cells may lead to deficiencies in the humoral immune system, so can the defects in cytotoxic T-cells lead to deficiency in the cell-mediated immunity.
In an immune deficiency condition, called DiGeorge syndrome, the mature thymus gland is absent in an affected individual. As a result, cell- mediated immunity is seriously affected and the person becomes highly susceptible to infections by fungi, viruses and protozoa. As cytotoxic T-cells chiefly provide immunity against intracellular pathogens and large parasites, their absence or depletion in number makes the immuno-deficient persons specially susceptible to those pathogenic agents.
Another immune deficiency disease, known as severe combined immunodeficiency, results from inherent defects in the precursor stem cells from which B-cells and T-cells are formed. The defense of the body against external agents may also be seriously affected due to defects in the phagocytic cells and in the process of phagocytosis itself. Removal of non-self antigens by phagocytosis is one of the most important mechanisms in both innate and acquired defense.
Defects in phagocytes may be due to inherent abnormalities in the stem cells which give rise to the monocytes and polymorphonuclear cells. The defect may result in abnormal reduction in number of phagocytes or may affect the process of phagocytosis. In a type of immune deficiency, known as neutropenia, a person has too few neutrophils. In another disease, called Chediak-Higashi syndrome, the phagocytic process is defective in that the fusion of a phagosome and lysosome in the phagocytic cell does not take place.
As a result, the lysosomal enzymes are not released to kill the ingested pathogen. In still another type of defect involving margination, the phagocytes lose the ability to transmigrate from the capillaries into tissues, so that they cannot reach the site of inflammation.
For transmigration, the neutrophils and monocytes must first adhere to the endothelial cells of capillaries. This requires a protein, known as adhesion factor. In defective leucocytes, this adhesion factor is lacking.
Apart from the congenital defects in the cellular components, immune deficiency may be due to abnormal or absence of one or more of the complement proteins. These proteins play a variety of important roles in both innate and acquired defense of the body. Of special importance is a defective C3 complement component.
A person deficient in this protein becomes highly susceptible to recurrent infection of capsulated pathogens like Streptococcus, Neisseria etc. This is due to the fact that the subcomponent C3b is an important opsonin which binds to both the bacterial surface antigens as well as to the specific receptors of neutrophils, thereby facilitating phagocytosis of the microbial cells.
Similarly, deficiency in other complement components, like CI, C2 etc., leads to defects in elimination of antigen-antibody complexes and may cause diseases like lupus (SLE). Again, defects in the complement components which build up the membrane attack complex causing cytolysis of microbes necessarily increase the susceptibility of the affected person to microbial pathogens.
(ii) Acquired Immune Deficiency:
Immune deficiency may be acquired through the normal process of aging or senescence, or by infection of the retroviruses — human immunodeficiency viruses (HIV-1 and HIV-2). Infection by HIV leads to the development of the currently most dreadful infectious disease, acquired immunodeficiency syndrome (AIDS).
Immune deficiency acquired by aging develops due to senescence of the immune system which becomes less responsive to foreign antigens. In particular, T-cell function deteriorates with aging due to the lack of an active thymus-gland. This gland is gradually replaced by fat with aging and, after the age of 60 or so, a person has to depend on T-cells produced earlier, because fresh T-cell formation stops.
Similarly, humoral immunity also shows senescence-associated changes. B-cell production in bone-marrow subsides and, more importantly, the antibodies produced by them show a decreased affinity to antigens. B-cell activation which requires participation of T-helper cells also declines, because of decrease in T-cell population.
Thus, the combined effects of the cell-mediated and the antibody-mediated immunity contribute to the senescence of the overall immune system. As a result, elderly persons become more susceptible to infectious diseases.
Besides the intrinsic factors related to aging, other external factors may exert adverse effects on the immune system producing immune deficiency. Among these factors, two important ones are malnutrition and application of cytotoxic drugs.
Malnutrition caused by protein deficiency may affect the normal development of the immune- responsive cells and molecules at any age. Similarly, lack of certain metal ions — like iron and zinc in the diet — may have an adverse effect on the development of immune system.
Cytotoxic drugs and other physical agents used to kill or suppress tumour cells profoundly affect the overall immune system. These anti-tumour agents not only kill the target cells, but also cells essential for the immune-function, like the stem cells and different types of leucocytes.
Acquired immunodeficiency syndrome (AIDS):
The most important among the acquired immunodeficiency diseases is AIDS. About 50 million people are suffering from AIDS at present (2005) throughout the world, with 10% of them (5 million) in India. The main causal agent is HIV-1 which is worldwide in distribution.
A second virus, HIV-2, mainly restricted to West Africa, also leads to development of AIDS, but more slowly than HIV-1. Both viruses belong to the class Retrovirus (also known as lentiviruses) and produce DNA in the infected cells from the genomic RNA consisting of two identical molecules. The virions contain the enzyme reverse transcriptase required for making DNA from the viral RNA.
The virions are enveloped and contain spikes of glycoproteins having molecular weight of 120 kd. With the help of these glycoprotein spikes, technically designated as gp 120 the virions bind to specific receptors present on target cells.
HIVs probably originated from the Simian immunodeficiency virus (SIV) which infects monkey and chimpanzee. The probable location of origin of HIV is thought to be central Africa. SIV has more similarity to HIV-2 than HIV-1.
The disease known as AIDS is the consequence of HIV infection, though there is usually a long gap between infection and the manifestation of symptoms. AIDS was first detected by the Centre for Disease Control and Prevention, Atlanta, USA in June, 1981 among a group of 5 gay men suffering from an unusual and rare pneumonia caused by a bacterium, Pneumocystis carinii and a type of skin cancer, called Kaposi’s sarcoma. The association of these diseases with a virus was suspected and the virus was first identified in 1984. It was officially designated as human immunodeficiency virus (HIV) in 1986.
HIV attacks specifically cells having CD4 receptors. These receptor proteins are present on the surface of T-helper cells, both TH-1 and TH-2, as well as on macrophages and dendritic cells. Apart from the CD4 receptors, co-receptors are also required for binding of HIV to target cells.
The co-receptors are specific surface proteins of target cells which act as receptors of cytokines under normal conditions. The co-receptor on T-cells are CXCR4 and those on macrophages are CCR5, where CC means two adjacent cystein residues at the beginning of the polypeptide of the co-receptor protein. CXC means two cystein molecules intervened by another amino acid (X).
The HIV virion binds to the target cell receptor-co-receptor complex with the help of its glycoprotein spikes (gp 120) as shown diagrammatically in Fig. 10.62:
After entry into the target cell, viral RNA is released by un-coating and it is transcribed into complementary ds-DNA with the help of viral reverse transcriptase. The DNA is then integrated into one of the chromosomes of the target cell and becomes a provirus. In the provirus state, the virus is no longer susceptible to the attack of the immune system of the body, but it retains the capacity to produce new virus particles.
These progeny virus particles can attack macrophages where they hide as latent virions in the vacuoles of these cells. Either as provirus or latent virus, HIV can evade the HIV- antibodies produced by the body in response to the HIV. Though HIV-antibodies are produced in the serum of the infected person, free viruses are not present in the blood stream at this stage of infection.
Another important feature of all retroviruses including HIVs is rapid change of antigenic specificity due to high rate of mutation. This property of retroviruses is due to their reverse- transcriptase activity which is used for transcribing virion-genome into pro-viral DNA.
In normal DNA replication by DNA-polymerase, the chance of incorporation of a wrong nucleotide in the elongating DNA molecule is eliminated by a corrective mechanism, called proof-reading, by the epsilon subunit of the DNA-polymerase molecule. The reverse-transcriptase lacks such a proof-reading mechanism. As a result, DNA transcribed from RNA contains numerous nucleotide replacements which cause genetic variations in retroviruses.
This inherent property of HIV has given rise to a large number of genetically distinct groups within HIV-1. These groups are called clades. The presence of many clades makes it difficult to develop strategies of control of these viruses either with drugs or by vaccination.
Development of symptoms of AIDS takes about 10 years from the initial infection by HIV in case of adults. The most common symptoms of fully developed AIDS are various infections caused by opportunistic organisms. These include Pneumocystis carinii causing an uncommon type of pneumonia, a number of fungi, like Candida, Cryptosporidium, Cryptococcus etc. and a virus, human herpes virus (HHV8), causing a type of cancer, Kaposi’s sarcoma.
An AIDS patient falls prey to such opportunistic pathogens, because of total failure of the immune system (immunodeficiency) which increases gradually as the disease progresses. At the initial stage of infection, the loss of the main target cell which is CD4+ -cells is compensated by continuous production of fresh cells by the immune system.
With progress of the infection, the production of fresh T-cells cannot keep pace with loss of T-cells resulting from attack of HIV. The consequence is rapid reduction of T-cells. In a normal individual, the number of T-cells per microlitre of blood is about 1,000. This number often falls to less than 100 in an advanced AIDS patient.
The total break-down of the immune system in an AIDS patient is due mainly to the destruction of CD4+ T-cells i.e. TH-cells. These cells play a central role in both antibody-mediated, as well as in cell- mediated immunity (Fig. 10.63). In humoral immunity, TH-cells bind to B-cells and secrete cytokines which induce proliferation, activation and transformation of B-cells into antibody-manufacturing plasma cells. TH-cells also activate macrophages by secreting specific cytokines.
Loss of this activity affects phagocytosis and antigen-presentation functions of macrophages as well as of dendritic cells. Besides, the virus can also directly attack these cells which possess CD4 receptors. TH-cells are essential for activation of CD8+ T-cells into cytotoxic T-cells. Thus, depletion of TH-cells also produces adverse effects on cell-mediated immunity. It is easily understandable, therefore, that the destruction of TH-cells by HIV leads to an overall disruption of the whole immune system in an AIDS patient who becomes helpless to the attack of various pathogenic agents and finally succumbs to one or more of the infectious diseases.