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Chapter 13: Failures of the Body's Defenses
Terms in this set (61)
any inherited or acquired disorder in which some part or parts of the immune system are either absent or defective, resulting in failure to mount an effective immune response to pathogens
antigenically different strain of a bacterium or other pathogen that can be distinguished by immunological means, for example by antibody-based detection tests. Also used to describe different types of human alloantigen such as HLA and blood group antigens.
Genetic variation within some species of pathogens prevents what?
Genetic variation within some species of pathogens prevents long-term immunity. Antibodies directed against macromolecules on the surface of pathogens are the most important source of long-term protective immunity to many infectious diseases. Some species of pathogen evade such protection by existing as numerous different strains, which differ in the antigenic macromolecules on the outer surface. S. pneumonaie have over 90 serotypes
What allows the influenza virus to escape immunity?
Mutation and recombination allow influenza virus to escape from immunity. Influenza evolves new varients through antigenic drift or antigenic shift
outbreak of infectious disease that affects many individuals within a population
process by which point mutation in influenza virus genes cause alterations in the structure of viral surface antigens. This causes year-to-year antigenic differences in strains of influenza virus.
outbreak of an infectious disease that spreads worldwide. For example, "Spanish flu" following world war 1. New pandemic strains of viruses can often arise recombination of avian and human RNA combine and have a new form of hemagglutinin
process by which influenza viruses reassort their segmented genomes and change their surface antigens radically. New viruses arising by antigenic shift are the usual cause of influenza pandemics.
Hemagglutination can be used to identify RBC surface antigens (with known antibodies) or to screen for antibodies (with RBCs with known surface antigens).
Trypanosomes use what to change their surface antigens?
Trypanosomes use gene conversion to change their surface antigens. Trypanosome genome contains more than 1000 genes encoding these variable surface glycoproteins (VSG). At any time, an individual trypanosome produces only one form of VSG. Rearrangement occurs by a process of gene conversion in which the gene in the expression sire is excised and replaced by a copy of a different but homologous gene.
variable surface glycoproteins (VSG)
any of a family of glycoproteins that form the surface coat of African trypanosomes. The trypanosome can repeatedly change its glycoprotein coat by expressing different glycoprotein genes by a process akin to gene conversion.
process whereby one copy of a gene, or part of a gene, is replaced by a different version of that gene, or part of that gene. A dominant form of VSG exists in the pathogen. A small minority has changed the expressed VGS gene and not expresses other forms. The host makes an antibody response to the dominant form of VSG, but not to the minority forms. Antibody-mediated clearance of trypanosomes expressing the dominant VSG facilitates growth of those expressing the minority forms, one of which will come to dominate the trypanosome population In time, the number of trypanosomes expressing the new dominant form is sufficient to stimulate the production of antibodies, which clear the new dominant form. This allows a further form to dominate, and so the cycle continues.
Salmonella typhimurium and neisseria gonorrhoeae also use gene conversion.
dormant state of some viruses that does not cause disease.
uses persistence and reactivation of herpes simplex virus to go into latent phase and then activation of infection.
How does herpes simplex virus operate
cause of cold sore. First infects epithelial cells and then spreads to sensory neurons serving the area of infection. The immune response clears virus from the epithelium, but the virus persists in a latent state in the sensory neurons. Various types of stress can reactivate the virus. After reactivation, the virus travels down the axons of the sensory neurons and reinfects the epithelial tissue. Viral replication in epithelial cells and the production of viral peptides restimulates CDD8 T cells, which kill the infected cells, creating a new sore. This cycle can be repeated many times throughout life. Neurons are a favored site for latent viruses to lurk because they express very small numbers of MHC class I molecules, further reducing the potential for presentation of viral peptides to CD8 T cells.
caused by the herpesvirus varicella-zoster. It remains latent in one or a few ganglia, chiefly dorsal root ganglia, after the acute infection of epithelium-- chickenpox-- is over. Stress of immunosuppresion can reactivate the virus, which then moves down the nerve and infects the skin. The disease caused by the reactivation of varicella-zoster is commonly known as shingles. Reactivation of varicella-zoster usually occurs once in a lifetime, unlike herpes simplex virus.
Epstein-Barr virus (EBV)
a third type of herpesvirus that causes persistent infection. EBV infects B cells by binding to the CR2 component of the B-cell coreceptor complex. Even after the immune system clears the virus, the virus persists in the body because a minority of B cells become latently infected. This involves shutting of synthesis of most viral proteins except EBNA-1, which maintains the viral genome in these cells. Latently infected cells do not present a target for attack by CD8 cytotoxic cells because the proteasome is unable to degrade EBNA-1 into peptides that are bound and presented by MHC class I molecules.
After recovery from initial exposure to EBV, it is unlikely for reactivation to cause disease.
Examples of pathogens that sabotage or subvert immune defense mechanisms
1. Myobacteria tuberculosis: commandeers the macrophages's pathway of phagocytosis for its own purposes. On being phagocytosed, M. tuberculosis prevents the fusion of phagosome and lysosome. It then survives and flourishes within the cell's vesicular system.
2. Toxoplasma gondii: parasite that creates its own specialized environment within the cells that it infects. This protozoan encloses itself in an impermeable membrane-enclosed vesicle that does not fuse with other vesicles or membranes of the cell. Prevents presentation by MHC molecules and T cell activation.
3. Treponema palladium: cause of syphilis. evades specific antibody by coating itself with human proteins. This is also a strategy pursued by the schistosome, a parasitic helminth worm.
Which of the four groups of pathogens have evolved the greatest variety of mechanisms for subverting or escaping immune defenses?
Viruses have evolved the greatest variety of mechanisms for subverting or escaping immune defenses. This is because their replication and life cycle depend completely on the metabolic and biosynthetic processes of human cells. Viral self-defense strategies include the capture of cellular genes encoding cytokines, which then expressed by the virus can divert the immune response. The synthesis of proteins that inhibit complement fixation, and the synthesis of proteins that inhibit antigen processing and presentation by MHC class I molecules.
herpesvirus human cytomegalovirus.
has 10 proteins that interfere in diverse ways to diminish the capacity of MHC class I molecules to stimulate NK-cell and CD8 T cell responses against CMV-infected cells, such as interfering with the TAP or tapasin proteins, by interfering with the proteasome, by causing their degradation, or by retaining the MHC class I molecules in the endoplasmic reticulum. A second group of saboteurs interfere with inhibitory NK-cell receptors CD94LNKG2D and LILRB1, which sense missing self-MHC class I, and with activating NKG2D receptor, which recognized the ligands MIC and ULBP.
molecule that, by binding nonspecifically to MHC class II molecules and T-cell receptors, stimulates the polyclonal activation of T cells. Small bacterial protein toxins that activate many different T cell clones. Bacterial superantigens activate CD4 T cells by cross linking MHC class II molecules with alpha:beta T -cell receptors and CD28 co-stimulatory molecules in the absence of antigenic peptides
toxic shock syndrome toxin-1 (TSST-1)
superantigen secreted by Staphylococcus aureus that cause toxic shock, a systemic shock reaction resulting from the overproduction of cytokines by CD4 T cells activated by the superantigen.
Activates Vbeta2 gene segment of CD4T cells.
S. aureus enterotoxin B (SEB)
a toxin secreted by strains of staphylococcus that acts on the gut to cause the symptoms of food poisoning. It is also a superantigen. Activates Vbeta1.1, 3.2, 6.4 and 15.2 CD4 T cells.
Staphlyococcal superantigen-like proteins (SSLPs)
family of structurally related superantigens that subvert and compromise human immunity in a variety of ways. The purpose of SSLP7 is to prevent monomeric IgA from delivering the bacterium to phagocytes. In the absence of SSLP7, IgA binds to a bacterium with its Fab arms to FcalphaRI on neutrophils and macrophages with its Fc region. This activates the phagocyte to engulf and destroy the bacterium bound to the Fc receptor. SSLP7 has binding sites for the Fc region of IgA and for the C5 complement protein. These interactions create a large constrained complex in which IgA binding to FcalphaRI and complement mediated killing of the bacterium are both prevented.
The purpose of SSLP7 is to prevent monomeric IgA from delivering the bacterium to phagocytes. In the absence of SSLP7, IgA binds to a bacterium with its Fab arms to FcalphaRI on neutrophils and macrophages with its Fc region. This activates the phagocyte to engulf and destroy the bacterium bound to the Fc receptor. SSLP7 has binding sites for the Fc region of IgA and for the C5 complement protein. These interactions create a large constrained complex in which IgA binding to FcalphaRI and complement mediated killing of the bacterium are both prevented.
primary immunodeficiency diseases
disease in which there is a failure of immunological function as a result of a defect in one or more genes encoding components of the immune system.
secondary immunodeficiency diseases
disease in which there is a failure of immunological function as a result of an infection of the use of immunosuppresive drugs, rather than as a result of defects in genes encoding components of the immune system
Mechanisms of human immunity are revealed by what?
Mechanisms of the human immunity are revealed by the study of inherited immunodeficiency syndrome
IFN-gamma is the major cytokine that activates macrophages, and is made by NK cells during the innate immune response and by TH1 CD4 T cells and CD8 cytotoxic T cells during the adaptive immune response. When IFN-gamma binds to IFN-gamma receptors on a macrophage surface, the cell is induced to make changes in gene expression and become better at engulfing and killing bacteria.
IFN-gamma receptor deficiency, recessive allele
Prevent any expression of IFNgammaR1 at the cell surface. The macrophage and monocyte of patients with two recessive alleles carry only IFNgammaR2 at their surfaces and are unresponsive to IFNgamma. For this group disease is usually more severe and appears at an earlier age. Heterozygotes are healthy because the protein made from the defective allele does not interfere with that made from the normal allele, which assembles with IFNgammaR2 and moves to the cell surface as functional IFN-gamma receptor.
IFN-gamma receptor deficiency, dominant allele
In the dominant mutation, IFNgammaR1 is truncated such that much of the cytoplasmic tail, which binds Jak1 and initiates signaling is missing. The truncated IFNgammaR1 associated with IFKgammaR2 protein and is taken to the surface as a receptor that binds IFK-gamma but cannot transduce a signal. At the cell surface, these defective receptors compete for IFN-gamma with the normal receptors that incorporate IFNgammaR1 made from the normal allele. This competition is further weighted against the functional receptors because the absence of the cytoplasmic domain from IFNgammaR1 prevent the mutant receptor from being recycled by endocytosis. It therefore accumulates at the cell surface, at levels fivefold higher than the normal receptor. Becayse of the interference of mutant receptors, the response of patients' macrophages and monocytes to IFN-gamma is much reduced compared to healthy people, but it is much greater than in patients carrying two recessive alleles. Dominant mutants cause a less sever immunodeficiency, which tends to be detected at a later age.
What is the major threat to patients lacking antibodies?
Infection by pyogenic (pus forming) bacteria. These encapsulated bacteria, which include H. influenzae, S. pneumoniae, S. pyogenes, and S. aureus, are not recognized by the phagocytic receptors of macrophages and neutrophils, so they frequently escape immediate elimination by the innate immune response. Such infections are usually cleared when the bacteria are opsonized by specific antibody and complement and then taken up and killed by phagocytes. For patients lacking antibodies, infections with pyogenic bacteria tend to persist unless treated with antibiotics.
X-linked agamaglobulinemia (XLA)
genetic disorder in which B-cell development is arrested at the pre-B-cell stage and neither mature B cells nor antibodies are formed. The disease is due to a defect in the gene encoding the protein tyrosine kinase BTK, which is located on the X chromosome.
Bruton's tyrosine kinase (BTK)
The gene that has a defect in the XLA disease. BTK contributes to the intracellular signaling from the B-cell receptor and is necessary for the development and differentiation of pre-B cells.
chronic inflammation of the bronchioles of the lung. Can be cause in XLA patients. To avoid this, XLA patients are given monthly injections of intravenous immunoglobulin. Intravenous immunoglobulin contains antibodies against common pathogens and provides passive immunity.
What is the result of defective genes encoding the membrane associated CD40 ligand?
Diminished production of antibodies because CD40 ligand is a component on T cells that needs to bind to CD40 on B cells in order to activate them. CD40 ligand is encoded on the X chromosome, so most patients with a hereditary deficiency in CD40 ligand are male.
X-linked hyper-IgM syndrome
genetic immunodeficiency disease in which B cels cannot switch their immunoglobulin heavy-chain isotype, and so make unusually high amounts of IgM and no other isotypes. It leads to abnormal susceptibility to infections with pyogenic bacteria, particularly in the sinuses, ears, and lungs. It can be due to several different underlying mutations. Also called hyper IgM immunodeficiency.
Like XLA patients, regular infusions of intravenous immunoglobulin help to prevent infections, and antibiotics are used to treat their infections.
condition in which there are increased number of leukocytes in the blood. It is commonly seen in acute infection.
a condition of abnormally low numbers of neutrophils in the blood, which can be due to various causes such as genetic deficiencies in neutrophil production, or autoimmunity directed against surface antigens on white blood cells.
Macrophage activation by effector CD4 T cells also depends on the interaction of CD40 on the macrophage with CD40 ligand on the T cell. In patients with X-linked hyper-IgM syndrome this interaction foes not occur, which impairs the macrophage production of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that stimulates the development of neutrophils in the bone marrow and their release into the circulation. People lacking CD40 ligand can be profoundly deficient in neutrophils, a state called neutropenia that often leads to sever sores and blisters in the mouth and throat.
Deficiency of complement C1, C2, C4
Deficiency of complement C3
Susceptibility to encapsulated bacteria (pyogenic infection)
Deficiency of complement C5-C9
Susceptibility to Neisseria
Deficiency of complement protein Factor D, properdin (Factor P)
Susceptibility to encapsulated bacteria and Neisseria but no immune-complex disease
Deficiency of complement protein Factor 1
Similar effects to deficiency of C3
Deficiency of complement protein DAF and CD59
Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria
Deficiency of complement protein C1INH
Hereditary angioedema (HAE)
immune complex disease
accumulation of the immune complexes in the blood.
Immune complexes: protein complex formed by the binding of antibodies to soluble antigens. The size of immune complexes depends on the relative concentrations of antigen and antibody. Large immune complexes are cleared by phagocytes bearing Fc and complement receptors. Small soluble immune complexes tend to be deposited on the walls of small blood vessels, where they can activate complement and cause damage.
Hereditary Angioedema (HAE)
genetic disease that results from deficiency of the C1 inhibitor of the complement system (C1INH). In the absence of C1 inhibitor, spontaneous activation of the complement system causes diffuse fluid leakage from blood vessels, the most serious consequences of which is epiglottal swelling leading to suffocation.
Treated with infusions of recombinant C1INH protein, some of which is purified from the milk and transgenic rabbits expressing the human C1INH gene.
C1 inhibitor (C1INH)
Regulatory protein in plasma that inhibits the enzyme activity of activated complement component C1. C1INH deficiency causes the disease hereditary angiodema, in which spontaneous complement activation causes episodes of epiglottal swelling and other symptoms.
class of protease inhibitor proteins that inhibit serine and cysteine proteases. The C1 inhibitor is an example of a serpin.
leukocyte adhesion deficiency
Syndrome due to the mutation of CD18 gene. Affects phagocytosis. Phagocytes are unable to engulf bacteria opsonized with complement. Children with this disease have persistent infection with pyogenic bacteria, respond poorly to antibiotics, and usually succumb during the first two years of life.
chronic granulomatous disease (CGD)
antibacterial activity of phagocytes is compromised by their inability to produce the superoxide radical O2-. Mutations affecting any of the four proteins with NADPH oxidase system can produce the phenotype. Patients suffer from chronic bacterial infections, often leading to granuloma formation.
phagocytosed materials are not delivered to lysosomes because of a defect in the vesicle fusion mechanism. The mutations causing this disease are in the CHS1 gene on chromosome 1, which encodes the lysosomal trafficking protein that is critical for lysosome function. Leads to persistent and re-occurring infection.
Severe Combined Immunodeficiency disease (SCID)
a sever immune deficiency disease in which neither antibody not T-cell responses are made. It is usually the result of genetic defects that lead to T-cell deficiencies, and is fatal in childhood if not teated with hematopoietic cell transplantation
Adenosine deaminase (ADA) deficiency or purine nucleoside phosphorylase (PNP) deficiency
ADA and PNP are enzymes involved in purine degradation. Deficiencies in these enzymes account for 15% of SCID patients. Autosomoally inherited.
common gamma chain
a protein chain that is the signaling component component of several cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15. When one of these cytokines bind to its receptor, common gamma chain interacts with the protein kinase Jak3 to produce intracellular signals. In the absenc of gamma chain, none of the 5 cytokines can induce signaling, so SCID results.
Wiskott-Aldrich syndrom (WAS)
A syndrome involving the platelets as well as the lymphocytes. It shows up in childhood as a history of recurrent infections but is less immunologically severe than SCID. Patients have normal levels of T and B cells but cannot make good antibody responses and are therefore kept on a course of intravenous immunoglobulin. The relevant gene on the X-chromosome encodes the Wiskott-Aldrich syndrome protein (WASP). This protein is involved in the cytoskeletal reorganization that is needed before T cells can deliver cytokines and signals to the B cells, macrophages, and other target cells with which they can form cognate interactions during development and participation in the immune response.
MHC Class II deficiency
A genetically determined immunodeficiency in which MHC class II molecules are not produced and which results in a lack of CD4 T-cell function
MHC Class I deficiency
rare genetically determined immunodeficiency in which MHC class I molecules are not present on cell surfaces, as a result of nonfunctional TAP proteins. The result is a deficiency of CD8 T cell function. Also known as bare lymphocyte syndrome type I. Less severe than MHC Class II deficiency.
IL-12 receptor deficiency
X-linked lymphoproliferate syndrome
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