chapter 12
course of HIV in body?
1) infects the CD4 t cells and dendritic cells in blood and mucosa 2) then gets transported to lymhoid tissues 3) the spread of infection throughout the body leads to viremia so anti HIV antibodies and HIV specific CTLs are created so there is partial control of the viral replication 4) then there is latency - establishment of chronic infection, virus trapped in lymphoid tissues by follicular dendritic cels, low level virus production 5) but then there are other microbial infections, cytokines and therefore increased viral replication 6) this leads to AIDs which is the destruction of the lymhoid tissue and depletion of CD4+ T cells
purpose of viral reverse trasncriptase?
A DNA copy of the viral RNA is synthesized by the viral reverse transcriptase enzyme (a process characteristic of all retroviruses)
elite controllers of HIV?
A small fraction of patients control HIV infection without therapy; these individuals are often referred to as elite controllers or long-term nonprogressors. There has been great interest in defining the genes that may protect these individuals, because elucidation of these genes may suggest therapeutic approaches. The presence of certain HLA alleles, such as HLA-B57 and HLA-B27, seems to be protective, perhaps because these HLA molecules are particularly efficient at presenting HIV peptides to CD8 + T cells.
what occurs in ADA and PNP deficiencies?
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).
what is 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
AIDS people susceptible to what?
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.
AIDS and HIV?
Although acquired immunodeficiency syndrome (AIDS) was first recognized as a distinct entity in the 1980s, it has become one of the most devastating afflictions in history. AIDS is caused by infection with HIV. Of the estimated 35 million HIV-infected people worldwide, about 70% are in Africa and 20% in Asia. More than 25 million deaths are attributable to HIV/AIDS, with 1 to 2 million deaths annually. Effective antiretroviral drugs have been developed, but the infection continues to spread in parts of the world where these therapies are not widely available, and in some African countries, more than 30% of the population has HIV infection.
what makes up an HIV particle?
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. HIV-1 consists of two identical strands of RNA (the viral genome) and associated enzymes, including reverse transcriptase, integrase, and protease, packaged in a cone-shaped core composed of the p24 capsid protein with a surrounding p17 protein matrix, all surrounded by a phospholipid membrane envelope derived from the host cell. Virally encoded envelope proteins (gp41 and gp120) bind to CD4 and chemokine receptors on the host cell surface. B, The HIV-1 genome consists of genes whose positions are indicated here as different-colored blocks. Some genes contain sequences that overlap with sequences of other genes, as shown by overlapping blocks, but are read differently by host cell RNA polymerase. Similarly shaded blocks separated by lines ( tat, rev ) indicate genes whose coding sequences are separated in the genome and require RNA splicing to produce functional messenger RNA. The major functions of the proteins encoded by different viral genes are listed.
scid mutations with JAK 3 and RAG 1 and 2?
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, described previously. 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
how do mmune responses to HIV paradoxically promote spread of the infection?
Antibody-coated viral particles may bind to Fc receptors on macrophages and follicular dendritic cells in lymphoid organs, thus increasing virus entry into these cells and creating additional reservoirs of infection. If CTLs are able to kill infected cells, the dead cells may be cleared by macrophages, which can migrate to other tissues and spread the infection. By infecting and thus interfering with the function of immune cells, the virus is able to prevent its own eradication.
what are the types of immmunodeficiencies?
B cell, T cell, and innate immune deficiecnies
why are antibodies not very functional against HIV?
But these immune responses usually do not prevent progression of the disease. Antibodies against envelope glycoproteins, such as gp120, may be ineffective because the virus rapidly mutates the region of gp120 that is the target of most antibodies.
what do gp41 and gp120 bind to on the t cell?
CD4 and chemokine receptors (CXCR4 and CCR5)
what can occur between macrophages and activated macrophages?
CD40L mutations (x linked hyper IgM syndrome)
why are CTLs not effective against HIV?
CTLs often are ineffective in killing infected cells because the virus inhibits the expression of class I MHC molecules by the infected cells.
what occurs in clinical 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
what is CVID?
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.
what are the causes of congenital immunodeficiecies?
Congenital immunodeficiencies are caused by genetic defects that lead to blocks in the maturation or functions of different components of the immune system Some of these disorders result in greatly increased susceptibility to infections that may manifest early after birth and may be fatal unless the immunologic defects are corrected. Other congenital immunodeficiencies lead to mild infections and may first be detected in adult life.
cytokines produced in response to HIV?
Cytokines produced in response to HIV and other microbes serve to enhance HIV production and progression to acquired immunodeficiency syndrome (AIDS)
complement deficiencies?
Deficiencies of almost every complement protein, and many complement regulatory proteins, have been described (see Chapter 8 ). 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.
what are immunodeficiency diseases
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
what is latency in HIV?
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 mm 3 (normal level about 1500 cells/mm 3 ), patients become susceptible to infections and are diagnosed as having AIDS.
what is 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.
IgA deficiency?
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.
what is the pathway of the T cell?
HSC to CLP CLP to Pro-T with (yc, JAK3, ADA, PNP) Pro-T to Pre-T with (VDJ recombination - RAG1, RAG2, ARTEMIS) Pre-T goes to CD4+ and CD8_ T cells double positive with (CD3 in the Pre-TCR checkpoint) CD4+ CD8+ double positive T cells go to CD8+ with ZAP 70, TAP1 and 2, and to CD4+ with MHC class 2
what is the pathway of a B cell?
HSC to CLP Pro B gets to Pre B with (VDJ recombination: RAG1, RAG2, ARTEMIS) Pre B gets to immature B with (BTK at the pre-BCR checkpoint) immature B goes to mature B cell
purpose of viral protease?
Here the virus is uncoated by viral protease, and its RNA is released.
what is 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.
what can occur between ativated t cells and th1?
IL-12R IFNyR mutations
what is leukocyte adhesion deficiency?
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.
what are acquired or secondary immunodeficiecnes?
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
t cell deficiency and mutations in signaling pathways?
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.
what kind of person can evade HIV?
Rare individuals with CCR5 mutations that do not permit HIV entry into CD4 + T cells can remain disease free for years after HIV infection.
TLR deficiencies?
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. For example, mutations affecting MyD88, an adaptor protein downstream of many TLRs, are associated with severe bacterial (most often pneumococcal) pneumonias, and mutations affecting TLR3 are associated with recurrent herpesvirus encephalitis but apparently not other viral infections. These quite restricted clinical phenotypes suggest considerable redundancy in host defense mechanisms, so defects in one pathway can be compensated by other pathways, and patients are not susceptible to a wide variety of infections.
what can occur between ativated t cells and th17?
STAT 3 mutations
what occurs in digeorgic 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.
what can be infected by HIV?
T cells, macrophages and dendritic cells
what is 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 (see Chapter 6 , Chapter 7 ). Failure to express functional CD40L leads to defective T cell-dependent B cell responses, such as isotype switching and affinity maturation, in humoral immunity, and to defective T cell-dependent macrophage activation in cell-mediated immunity. Boys with this disease are especially susceptible to infection by Pneumocystis jiroveci , a fungus that survives within phagocytes in the absence of T cell help. A rare autosomal recessive form of hyper-IgM syndrome is seen in subjects with mutations affecting the enzyme activation-induced deaminase (AID), which is involved in isotype switching and somatic hypermutation
purpose of current HIV treatments?
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.
T cells lost in HIV? dendritic and macrophage loss?
The depletion of CD4 + T cells after HIV infection is caused by a cytopathic effect of the virus, resulting from production of viral particles in infected cells, as well as death of uninfected cells. Active viral gene expression and protein production may interfere with the synthetic machinery of the T cells. Therefore, infected T cells in which the virus is replicating are killed during this process. The number of T cells lost during the progression to AIDS is greater than the number of infected cells. The mechanism of this T cell loss remains poorly defined. One possibility is that T cells are chronically activated, perhaps by infections that are common in these patients, and the chronic stimulation culminates in apoptosis. Other infected cells, such as dendritic cells and macrophages, may also die, resulting in destruction of the architecture of lymphoid organs. Many studies have suggested that immune deficiency results not only from depletion of T cells but, in addition, from various functional abnormalities in T lymphocytes and other immune cells (dendritic cells and macrophages). The significance of these functional defects has not been established, however, and loss of T cells (followed by a fall in the blood CD4 + T cell count) remains the most reliable indicator of disease progression.
wht is a provirus?
The integrated viral DNA is called a provirus. if HIV
steps of HIV?
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 ). HIV infects cells by virtue of its major envelope glycoprotein, called gp120 (for 120-kD glycoprotein), which binds to CD4 and to particular chemokine receptors on human cells (mainly CXCR4 and CCR5). The major cell types that may be infected by HIV are CD4 + T lymphocytes, macrophages, and dendritic cells. After binding to cellular receptors, the viral membrane fuses with the host cell membrane, and the virus enters the cell's cytoplasm. Here the virus is uncoated by viral protease, and its RNA is released. A DNA copy of the viral RNA is synthesized by the viral reverse transcriptase enzyme (a process characteristic of all retroviruses), and the DNA integrates into the host cell's DNA by the action of the integrase enzyme. The integrated viral DNA is called a provirus. If the infected T cell, macrophage, or dendritic cell is activated by some extrinsic stimulus, such as another infectious microbe, the cell responds by turning on the transcription of many of its own genes and often by producing cytokines. A negative consequence of this normal protective response is that the cytokines, and the process of cellular activation itself, also may activate the provirus, leading to production of viral RNAs and then proteins. The virus is then able to form a core structure, which migrates to the cell membrane, acquires a lipid envelope from the host, and is shed as an infectious viral particle, ready to infect another cell. The integrated HIV provirus may remain latent within infected cells for months or years, hidden from the patient's immune system (and even from antiviral therapies, discussed later).
whatis 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. The disease is caused by mutations in the gene encoding a kinase called Bruton tyrosine kinase (BTK), resulting in defective production or function of the enzyme. The enzyme is activated by the pre-B cell receptor expressed in pre-B cells, and it delivers signals that promote the survival, proliferation, and maturation of these cells. The BTK gene is located on the X chromosome. Therefore, women who carry a mutant BTK allele on one of their X chromosomes are carriers of the disease, but male offspring who inherit the abnormal X chromosome are affected. In about a fourth of patients with X-linked agammaglobulinemia, autoimmune diseases, notably arthritis, develop as well. A link between an immunodeficiency and autoimmunity seems paradoxical. One possible explanation for this association is that BTK contributes to B cell receptor signaling and is required for central B cell tolerance, so defective BTK may result in the accumulation of autoreactive B cells.
how does HIV get to t cells?
The virus infects CD4 + T cells, dendritic cells, and macrophages at sites of entry through epithelia; in lymphoid organs such as lymph nodes; and in the circulation. In mucosal tissues at the sites of entry, there may be considerable destruction of infected T cells. Because a large fraction of the body's lymphocytes, and especially memory T cells, reside in these tissues, the result of the local destruction may be a significant functional deficit that is not reflected in the presence of infected cells in the blood or the depletion of circulating T cells. Dendritic cells may capture the virus as it enters through mucosal epithelia and transport it to peripheral lymphoid organs, where it infects T cells.
what is HAART and ART?
This therapeutic approach is called highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (ART). It has changed the clinical course of HIV infection, such that opportunistic infections (e.g. by Pneumocystis ) and some tumors (e.g. Kaposi's sarcoma, EBV-induced lymphoma), which were devastating complications in the past, are now rarely seen. In fact, treated patients are living quite long life spans and are dying of cardiovascular and other diseases that also afflict individuals who age without HIV (although they may be accelerated as a consequence of HIV infection, for unknown reasons). Even these highly effective drugs do not completely eradicate HIV infection. The virus is capable of mutating its genes, which may render it resistant to the drugs used, and reservoirs of latent virus are not eradicated by these drugs. Additional drugs that inhibit fusion of the virus with host cells have been developed.
what is hematopoietic stem cell transplanation?
Treatment of primary immunodeficiencies varies with the disease. SCID is fatal in early life unless the patient's immune system is reconstituted. The most widely used treatment is hematopoietic stem cell transplantation, with careful matching of donor and recipient to avoid potentially serious graft-versus-host disease. For selective B cell defects, patients may be given intravenous injections of pooled immunoglobulin (IVIG) from healthy donors to provide passive immunity. IVIG replacement therapy has provided enormous benefit in patients with X-linked agammaglobulinemia. Although the ideal treatment for all congenital immunodeficiencies is to replace the defective gene, this remains a distant goal for most diseases. Successful gene therapy has been reported in patients with X-linked SCID; a normal γc gene was introduced into their bone marrow stem cells, which were then transplanted back into the patients. In some of these patients, however, T cell leukemia has subsequently developed, apparently because the introduced γc gene was inserted near an oncogene and activated it. In all patients with these diseases, infections are treated with antibiotics as needed.
about half of SCID are what?
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. (Because the γc chain was first identified as one of the three chains of the IL-2 receptor, it is also called the IL-2Rγ chain.) When the γc chain is not functional, immature lymphocytes, especially pro-T cells, cannot proliferate in response to IL-7, which is the major growth factor for these cells. Defective responses to IL-7 result in reduced survival and maturation of lymphocyte precursors. In humans, the defect affects mainly T cell maturation (whereas in mice, B cells are also reduced). The consequence of this developmental block is a profound decrease in the numbers of mature T cells, deficient cell-mediated immunity, and defective humoral immunity because of absent T cell help (even though B cells may mature almost normally). Natural killer (NK) cells also are deficient, because the γc chain is part of the receptor for IL-15, the major cytokine involved in NK cell proliferation and maturation.
what occurs with B cell deficiencies?
absent or reduced follicles and germinal centers in lymphoid organs, reduced serum Ig levels -- pyogenic bacterial infections, enteric bacterial and viral infections
During the course of HIV infection, the major source of infectious viral particles is?
activated CD4 + T cells; dendritic cells and macrophages are reservoirs of infection.
what is the chediak higashi syndrome?
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.
what is the bare lymphocyte syndrome?
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.
what is chronic granulomatous disease?
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.
what is the wiskott aldrich syndrome?
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.
what is ataxia telangiectasia?
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 the main two components of innate immunity that are causes of immunodeficiency?
chronic granulomatous disease and leukocyte adhesion deficiency
what can occur between B cell with Th cell and the plasma cell with antibodies?
common variable immunodeficiency, AID mutations (autosomal hyper IgM syndrome, selective Ig isotype defects, CD40L mutations (x linked hyper IgM syndrome)
what is x linked agammaglobulinemia?
decrease in all serum Ig isotypes, reduced B cell numbers, block in maturation beyond pre-B cells because of mutation in BTK
autosomal recessive SCID due to other causes?
decreased T and B cells, reduced serum Ig - defective maturation of T and B cells, may be mutations in RAG genes and other genes involved in VDJ recmbinatino or IL-7R signaling
defects in Th17 differentiation?
decreased T cell mediated inflammaroty responses, mcocutaneous candidiasis, backterial skin absesses - rare cases due to mutations in genes encoding Stat 3, IL-17, IL-17R
defects in Th1 differentiation?
decreased T cell mediated macrophage activation, susceptibility to infection - rare cases due to utations encoding for the receptros for IL-12 or IFN-y
defects in T cell receptor complex expression or signaling
decreased T cells or abnormal ratios of Cd4+ and cd8+ subsets, decreased cel mediated immunity - rare cases due to mutations or deletions in genes encoding CD3 proteins, ZAP 70
irradiation and chemotherapy treatments for cancer?
decreased bone marrow precursors for all leukocytes
removal of spleen?
decreased phagocytosis of microbes
what is digeorge syndrome?
decreased t cells, normal B cells, normal or decreased serum Ig - anomalous development of 3rd and 4th branchial puches, leading to thymus hypoplasia
what can occur between naive T cells and activated T cells?
defects in TCR complex signalting, class 2 MHC deficiency
x linked hyper IgM syndrome?
defects in helpet T cell dependent B cell and macrophage activation due to mutations in CD40L
what occurs in Ig heavy chain deficiencies?
deficiency of IgG subclasse,s sometimes associated with absent IgA or IgE - chromosomal deletion involving Ig heavy chain locus at 14q32
HIV?
depletion of CD4 helper T cells
immunosuppression for graft rejection and inflammatory diseases
depletion or function impairment of lymphocytes
what makes up the virally encoded evelope protein?
gp41 and gp 120
defective class 2 MHC expression the bare lymphocyte syndrome?
lack of class 2 MHC expression and impaired CD4_ T cell activation -- defective cell mediated immunity and T cell dependent humoral immunity - mutations in genes encoding transcription factors required for class 2 MHC gene expression
what is an indicator of HIV progression?
loss of T cells (followed by a fall in the blood CD4 + T cell count) remains the most reliable indicator of disease progression.
what is an x linked scid?
markedly decreases T cells, normal or increased B cells and reduced sreum Ig - cytokine receptor common y chain gene mutations, defective T cell maturation due to lack of IL-7 signals
what occurs with T cell deficiencies?
may be reduced T cell zones in lymhoid organs, reduced DTH reactions to common antigens, deitive T cell proliferative responses to mitogens in vitro -- viral and other intracellular microbial infections, virus associated malignanices
protein calorie malnutrition
metabolic derangements inhibit lymphocyte maturation and function
autosomal recessive SCID due to ADA, PNP deficiency?
progressive decrease in T and B cells (mostly T) - ADA or PNP defieicnecy leads to accumulation of toxic metabolites in lymphocytes
what are the 3 enzymes in the HIV ?
protease, integrin, reverse transcriptase
common variable immunodefieicny?
reduced or no production of selective isotypes or subtypes and immunoglobulins, susceptibility to bacterial infections or no clinical problems -- due to mutations in receptors for B cel growth factors, co stimulators
involvement of bone marrow by cancers?
reduced site of leukocyte development
what is SCID?
severse combined immunodeficiecny 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.
what are congenital or primary immunodeficiencies?
some of these diseases may result from genetic abnormalities in one or more components of the immune system
purpose of viral integrase?
the DNA integrates into the host cell's DNA by the action of the integrase enzyme
x linked lymphoproliferative syndrome?
uncontrolled EBV induced B cell proliferation and CTL activation, defective NK cell and CTL function and antibody responses - mutations in gene encoding SAP (adaptor protein involved in signaling in lymphocytes)
what occurs with innate immune deficiecnies?
variable depending on which componenet of innate immunity is defective -- variable: pyogenic bacterial and viral infections
SCID is caused by what?
yc mutations, mutations in autosomal genes that encode proteins involved in nucleic acid metabolism, mutations of the gene invovled in signaling by the yc cytokine receptor cahin or also by mutations in RAG1 or RAG2
