Chapter 12: Congenital and Acquired Immunodeficiencies, Diseases Caused by Defective Immunity
Describe the life cycle of the HIV virus.
The life cycle of HIV consists of the following sequential steps: infection of cells, production of a DNA copy of viral RNA and its integration into the host genome, expression of viral genes, and production of viral particles (Fig. 12-8).
Describe AIDS
AIDS develops over many years as latent HIV becomes activated and destroys cells of the immune system. Virus production leads to death of infected cells, as well as to death of uninfected lymphocytes, subsequent immune deficiencies, and clinical AIDS (Fig. 12-9)
Abnormalities in two components of innate immunity, phagocytes and the complement system, are important causes of immunodeficiency. Name some of these immunodeficiencies.
Chronic granulomatous disease is caused by mutations in genes encoding subunits of the enzyme phagocyte oxidase, which catalyzes the production of microbicidal reactive oxygen species in lysosomes (see Chapter 2). As a result, neutrophils and macrophages are unable to kill the microbes they phagocytose. The immune system tries to compensate for this defective microbial killing by calling in more macrophages and by activating T cells, which stimulate recruitment and activation of phagocytes. Therefore, collections of phagocytes accumulate around foci of infections by intracellular microbes, but the microbes cannot be destroyed effectively. These collections resemble granulomas, giving rise to the name of this disease. The most common form of chronic granulomatous disease is X-linked, caused by mutations in a subunit of the phagocyte oxidase enzyme that is encoded by a gene on the X chromosome. Leukocyte adhesion deficiency is caused by mutations in genes encoding integrins, molecules required for the expression of ligands for selectins, or signaling molecules activated by chemokine receptors required to activate integrins. Integrins and selectin ligands are involved in the adhesion of leukocytes to other cells. As a result of these mutations, blood leukocytes do not bind firmly to vascular endothelium and are not recruited normally to sites of infection. C3 deficiency results in severe infections and may be fatal. Deficiencies of C2 and C4, two components of the classical pathway of complement activation, may result in increased bacterial or viral infection or increased incidence of systemic lupus erythematosus, presumably because of defective clearance of immune complexes. Deficiencies of complement regulatory proteins lead to various syndromes associated with excessive complement activation. The Chédiak-Higashi syndrome is an immunodeficiency disease in which the lysosomal granules of leukocytes do not function normally. The immune defect is thought to affect phagocytes and NK cells and manifests as increased susceptibility to bacterial infection. Rare patients have been described with mutations affecting Toll-like receptors (TLRs) or signaling pathways downstream of TLRs, including molecules required for activation of the nuclear factor κB (NF-κB) transcription factor. Somewhat surprisingly, several of these mutations make patients susceptible to only a limited set of infections.
What is the difference between congenital (primary) and aquired (secondary) immunodeficiency?
Disorders caused by defective immunity are called immunodeficiency diseases. Some of these diseases may result from genetic abnormalities in one or more components of the immune system; these are called congenital (or primary) immunodeficiencies. Other defects in the immune system may result from infections, nutritional abnormalities, or medical treatments that cause loss or inadequate function of various components of the immune system; these are called acquired (or secondary) immunodeficiencies.
What is SCID?
Disorders manifesting as defects in both the B cell and T cell arms of the adaptive immune system are classified as severe combined immunodeficiency (SCID). Several different genetic abnormalities may cause SCID. • X-SCID caused by γc mutations. About half of the cases of SCID are X-linked, affecting only male children. More than 99% of cases of X-linked SCID are caused by mutations in the common γ (γc) chain signaling subunit of the receptors for several cytokines, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. • ADA and PNP deficiencies. Mutations in autosomal genes that encode proteins involved in nucleic acid metabolism cause many cases of SCID. About half the cases of autosomal recessive SCID are caused by mutations in an enzyme called adenosine deaminase (ADA), which is involved in the breakdown of adenosine. Deficiency of ADA leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA—namely, proliferating cells. Lymphocytes are particularly susceptible to injury by purine metabolites because these cells undergo tremendous proliferation during their maturation. ADA deficiency results in a block in T cell maturation more than in B cell maturation; defective humoral immunity is largely a consequence of the lack of T cell helper function. A similar phenotype is seen in individuals who have a deficiency in purine nucleotide phosphorylase (PNP). • Other mutations. Another important autosomal recessive form of SCID is caused by mutation of the gene encoding a kinase called JAK3 that is involved in signaling by the γc cytokine receptor chain. Such mutations result in the same abnormalities as those in X-linked SCID caused by γc mutations. Rare cases of autosomal recessive SCID are caused by mutations in the RAG1 or RAG2 gene, which encode the VDJ recombinase that is required for immunoglobulin (Ig) and T cell receptor gene recombination and lymphocyte maturation
Describe the Human immunodeficiency virus (HIV)
Human immunodeficiency virus (HIV) is a retrovirus that infects cells of the immune system, mainly CD4+ T lymphocytes, and causes progressive destruction of these cells. An infectious HIV particle consists of two RNA strands within a protein core, surrounded by a lipid envelope derived from infected host cells but containing viral proteins (Fig. 12-7). The viral RNA encodes structural proteins, various enzymes, and proteins that regulate transcription of viral genes and the viral life cycle.
Name and describe some of the immunodeficiencies caused by defects in B cell response.
Hyper-IgM Syndrome. The X-linked hyper-IgM syndrome is characterized by defective B cell heavy-chain isotype (class) switching, so IgM is the major serum antibody, and by deficient cell-mediated immunity against intracellular microbes. The disease is caused by mutations in the X chromosome gene encoding CD40 ligand (CD40L), the helper T cell protein that binds to CD40 on B cells, dendritic cells, and macrophages and thus mediates T cell-dependent activation of these cells Genetic deficiencies in the production of selected Ig isotypes are quite common. IgA deficiency is believed to affect as many as 1 in 700 people but causes no clinical problems in most patients. The defect causing these deficiencies is not known in a majority of cases; rarely, the deficiencies may be caused by mutations of Ig heavy-chain constant (C) region genes. • Common variable immunodeficiency (CVID) is a heterogeneous group of disorders that represent a common form of primary immunodeficiency. These disorders are characterized by poor antibody responses to infections and reduced serum levels of IgG, IgA, and often IgM. The underlying causes of CVID include defects in various genes involved in B cell maturation and activation. Some patients have mutations in genes encoding receptors for B cell growth factors or costimulators that play a role in T cell-B cell interactions. Patients have recurrent infections, autoimmune disease, and lymphomas
Name som inherited abnormalities thatmay interfere with T cell activation.
The bare lymphocyte syndrome is a disease caused by a failure to express class II major histocompatibility complex (MHC) molecules, as a result of mutations in the transcription factors that normally induce class II MHC expression. Recall that class II MHC molecules display peptide antigens for recognition by CD4+ T cells and this recognition is critical for maturation and activation of the T cells. The disease is manifested by a profound decrease in CD4+ T cells because of defective maturation of these cells in the thymus and poor activation of the cells in peripheral lymphoid organs. Rare cases of selective T cell deficiency are caused by mutations affecting various signaling pathways or cytokines and receptors involved in differentiation of naive T cells into effector cells. Depending on the mutation and the extent of the defect, affected patients show severe T cell deficiency or deficiency in particular arms of T cell-mediated immunity, such as in Th1 responses (associated with nontuberculous mycobacterial infections) and Th17 responses (associated with fungal and bacterial infections). These defects have revealed the importance of various pathways of T cell activation, but these are rare disorders.
Clinical features of HIV infection and AIDs
The clinical course of HIV infection is characterized by several phases, culminating in immune deficiency (Fig. 12-10, A). • Acute HIV syndrome. Early after HIV infection, patients may experience a mild acute illness with fever and malaise, correlating with the initial viremia. This illness subsides within a few days, and the disease enters a period of clinical latency. • Latency. During latency, there may be few clinical problems but usually there is a progressive loss of CD4+ T cells in lymphoid tissues and destruction of the architecture of these tissues. Eventually, the blood CD4+ T cell count begins to decline, and when the count falls below 200 cells per mm3 (normal level about 1500 cells/mm3), patients become susceptible to infections and are diagnosed as having AIDS. • Clinical AIDS. The clinicopathologic manifestations of full-blown AIDS are primarily the result of increased susceptibility to infections and some cancers, as a consequence of immune deficiency. Patients not given antiretroviral drugs often are infected by intracellular microbes, such as viruses, the fungal pathogen Pneumocystis jiroveci, and nontuberculous mycobacteria, all of which normally are combated by T cell-mediated immunity. Many of these microbes are present in the environment, but they do not infect healthy persons with intact immune systems. Because these infections are seen in immunodeficient persons, in whom the microbes have an opportunity to establish infection, these types of infections are said to be opportunistic. Many of the opportunistic infections are caused by viruses, such as cytomegalovirus. Patients with AIDS show defective cytotoxic T lymphocyte (CTL) responses to viruses, even though HIV does not infect CD8+ T cells. The CTL responses are defective probably because CD4+ helper T cells (the main targets of HIV) are required for full CD8+ CTL responses against many viral antigens (see Chapters 5 and 6). AIDS patients are at increased risk for infections by extracellular bacteria, probably because of impaired helper T cell-dependent antibody responses to bacterial antigens. Patients also become susceptible to cancers caused by oncogenic viruses. The two most common types of cancers are B cell lymphomas, caused by the Epstein-Barr virus, and a tumor of small blood vessels called Kaposi's sarcoma, caused by a herpesvirus. Patients with advanced AIDS often have a wasting syndrome with significant loss of body mass, caused by altered metabolism and reduced caloric intake. The dementia that develops in some patients with AIDS is likely caused by infection of macrophages (microglial cells) in the brain.
Describe the therapeutic approaches HAART abd ART.
The current treatment for AIDS is aimed at controlling replication of HIV and the infectious complications of the disease. Combinations of drugs that block the activity of the viral reverse transcriptase, protease, and integrase enzymes are now being administered early in the course of the infection. This therapeutic approach is called highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (ART).
Some systemic diseases that involve multiple organ systems, and whose major manifestations are not immunologic, may have a component of immunodeficiency. Name some of these.
Wiskott-Aldrich syndrome is characterized by eczema, reduced blood platelets, and immunodeficiency. This X-linked disease is caused by a mutation in a gene that encodes a protein that binds to various adaptor molecules and cytoskeletal components in hematopoietic cells. Because of the absence of this protein, platelets and leukocytes do not develop normally, are small, and fail to migrate normally. Ataxia-telangiectasia is characterized by gait abnormalities (ataxia), vascular malformations (telangiectasia), and immunodeficiency. The disease is caused by mutations in a gene whose product is involved in DNA repair. Defects in this protein lead to abnormal DNA repair (e.g., during recombination of antigen receptor gene segments), resulting in defective lymphocyte maturation.
What are some examples of immunodeficiencies that are caused by defects affecting eiher B or T cells.
X-Linked Agammaglobulinemia. The most common clinical syndrome caused by a block in B cell maturation is X-linked agammaglobulinemia (first described as Bruton's agammaglobulinemia). In this disorder, pre-B cells in the bone marrow fail to expand, resulting in a marked decrease or absence of mature B lymphocytes and serum immunoglobulins DiGeorge Syndrome. Selective defects in T cell maturation are quite rare. Of these, DiGeorge syndrome is the most frequent. It results from incomplete development of the thymus (and parathyroid glands). Patients with DiGeorge syndrome fail to develop mature T cells. The condition tends to improve with age, probably because the small amount of thymic tissue that does develop is able to support some T cell maturation.
