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100 Cards in this Set
- Front
- Back
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Failure of body defenses
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Evasion and subversion of the immune system by pathogens
Inherited deficiencies of the immune system Congenital (primary) deficiencies Deficiencies that are a consequence of other diseases or conditions Acquired (secondary) deficiencies |
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Pathogen escape
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Organisms that can escape or subvert the immune response can out-compete other pathogens to exploit the resources of the human body
Some of these organisms have evolved to possess genes devoted to escaping and/or evading the immune response |
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Genetic variation within some species prevents effective long term immunity
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Host Ab against molecules on microbe surface results in long-term protective immunity
Streptococcus pneumoniae Common cause of respiratory infections Variation of the capsule results in different strains (serotypes) Ab formed against one strain is not protective against other strains |
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Mutation and recombination
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Allows for repeated infections with the same organism
Ab against influenza virus bind to viral glycoproteins Hemagglutinin (H1N1: Spanish flu, Swine flu) Neuraminidase (H5N1: Avian flu) Mutations and recombination of the glycoproteins necessitates the need for production of new influenza vaccines each year 31 influenza pandemics since 1510 |
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Herpes viruses
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Virus first infects epithelial cells
Spreads to sensory neurons serving area of infection Virus persists in latent state Virus is reactivated due to stress Sunlight, bacterial or viral infection, hormonal changes virus travels along neurons and reinfects epithelial tissue |
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Sabotage and subversion of immune defense mechanisms
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Mycobacterium tuberculosis
Prevents fusion of macrophage phagosome with lysosome, protecting itself from action of bacteriocidal lysosmal contents Listeria monocytogenes Escapes from macrophage phagosome into the cytoplasm Organism then grows and replicates in cytoplasm |
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Sabotage and subversion of immune defense mechanisms
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Toxoplasma gondii
Surrounds itself with a membrane-bound vesicle Prevents binding to MHC molecules and presentation to T cells Treponema pallidum Coats itself with human proteins Evades Ab coating |
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Viruses
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Viruses have evolved the greatest variety of mechanisms for subverting or escaping immune defenses
virus replication and life cycle depend completely on the host cell metabolic and biosynthetic processes Viruses can inhibit humoral immunity Viruses can inhibit the inflammatory response |
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Viral self-defense strategies
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Capture of cellular genes encoding cytokines or cytokine receptors
When expressed by virus, can divert immune response Synthesis of proteins that inhibit complement fixation Synthesis of proteins that inhibit Ag processing and presentation by MHC class I molecules |
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Repeated or unusual infections suggest the presence of immunodeficiency
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Repeated or unusual infections suggest the presence of immunodeficiency
The type of opportunistic infection also gives clues to the cause and degree of the immunodeficiency |
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Defects in development and functions
of the immune system lead to |
Defects in development and functions
of the immune system lead to Increased susceptibility to infections Increased incidence of certain tumors Defects can be in either the innate or acquired immune system or both |
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General features of immunodeficiency
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Frequent, prolonged, severe infections
Increased opportunistic infections Organisms that are nonpathogenic in the complement host Kaposi’s sarcoma-associated herpesvirus Increased incidence of cancers |
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Types of defects
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Innate system defects include
Phagocytic defects Complement system defects Acquired system defects include Humoral (antibody) defects Cell-mediated defects Deficiency in each component may by congenital or acquired |
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Congenital deficiency
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Deficiency is the cause of the disease
Occurs in ~1 in 10,000 Categorized based on the clinical presentation which corresponds to the part of the immune system which is malfunctioning |
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Types of congenital deficiencies
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Antibody
T cell Combined antibody and T cell Phagocyte Complement |
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Congenital immunodeficiencies are
caused by |
Congenital immunodeficiencies are
caused by genetic defects that lead to blocks in the maturation or functions of different components of the immune system |
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Mutations
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affect any part of the immune system
Cause severe disease |
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Polymorphisms
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Very common traits
Affect any part of the immune system cause moderate increased risk of infections |
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Polygenic disorders
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Relatively common, affecting mainly Ab
Cause severe disease |
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Innate system defects
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Characterized by infections with extracellular pathogens
Phagocytosis defects Quantitative Qualitative Complement cascade defects |
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Phagocytic defects
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Pathogenesis varies in severity
Mild, recurrent skin infections Severe, overwhelming bacterial and/or fungal infections Patients usually respond normally to viral or protozoan infections Account for ~18% of immunodeficiencies |
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Quantitative phagocytic deficiencies
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Normal neutrophil count = 2500–8000 /μL
Disease is noted if count < 500-1000/ μL Intrinsic defects Genetic defect affecting myeloid stem cell during hematopoiesis Extrinsic defects Secondary to another disease or defect Drugs like chemotherapy Systemic disease (diabetes) Defects in other arms of the immune system that activate phagocytes (C3b or cytokines) |
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Qualitative defects
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May occur in any step of phagocytic action
Migration and adhesion Phagocytosis and formation of phago-lysosome Organism killing |
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Leukocyte adhesion deficiency (LAD)
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Group of disorders in which WBC interaction with vascular endothelium is disrupted
Patients suffer from recurrent soft tissue infections Increased WBC count without pus formation impaired wound healing |
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Chédiak-Higashi syndrome
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Autosomal recessive disease with poor prognosis
Abnormal giant granules and organelles in cells Lysosomes and melanosomes are chiefly affected leading to defects in Pigmentation (albinism) Neutrophil, platelet and NK cell function Neurologic function |
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Chédiak-Higashi syndrome
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Defective degranulation leads to decreased intracelular killing
Staph and Strep can cause recurrent, sometimes lethal infections |
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Chronic granulomatous disease of childhood (CGD)
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Rare, usually fatal syndrome
Affects 1 in 106 births in US Recurrent bacterial and fungal infections Several genetic defects with common phenotypic malfunction 60% are X-linked 40% are autosomal inheritance |
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CGD
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Inability to kill intracellular organisms
Defective or absent “respiratory burst” Generation of peroxide or superoxide radicals used to kill ingested organisms Formation of granulomas at infection site Treatment includes Aggressive immunization Wide spectrum antibiotic prophylaxis Anti-fungal drugs INF-γ (activates monocytes and NK cells) |
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IFN-γ receptor deficiency
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Inability of monocytes to respond to IFN-γ
Patients are susceptible to infections with mycobacteria other than M. tuberculosis Never immunize with BCG vaccine, have another infection |
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Complement deficiencies
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Genetically determined deficiencies have been described for all the complement components
Complement components are inherited as co-dominant alleles, each contributes 50% of normal protein levels Heterozygous = phenotypically normal Homozygous 0-10% of normal complement components Very susceptible to infections |
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Deficiencies of early complement components
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Early components are most important in opsonization
Increased infections due to decreased opsonization Rheumatic diseases due to improper immune complex clearance C3 deficiency results in most severe symptoms |
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Deficiencies of late complement components
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Interfere with generation of membrane attack complex (MAC)
MAC is important in lysis of Gram negative bacteria, especially Neisseria species Increased risk of meningitis |
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Defects in control of complement components
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Hereditary angioedema
C1Inh (C1 esterase inhibitor) deficiency Uncontrolled action of C1 on C2 and C4 Increased blood vessel permeability leading to edema Paroxysmal nocturnal hemoglobinuria Defect in decay accelerating factor (DAF) Spontaneous lysis of RBCs, especially at night |
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B cell or Ig deficiencies
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Range from defective B cell development (complete absence of all Ig) to deficiency of a particular class/subclass of Ig
Patients suffer from recurrent or chronic infections |
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Bruton’s X-linked agammaglobulinemia
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X-linked recessive disorder
Symptoms appear at ~5-6 months of age maternal Ab are depleted Serious, repeated bacterial infections Otitis media, bronchitis, septicemia, pneumonia, meningitis Little to no Ab of all classes |
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Bruton’s
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Defective gene produces non-functional tyrosine kinase
Inability of B cells to mature Absence of mature B cells and plasma cells in bone marrow, peripheral blood, spleen and lymph nodes Treatment Intravenous administration of Ig Antibiotic prophylaxis |
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Transient hypogammaglobulinemia
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Occurs at ~5-6 months of age, especially in premature infants
Inability to produce their own Ig Peripheral blood shows normal numbers of B cells Deficiency in number and function of Thelper cells may exist May persist for a few months – 2yrs Avoid immunizations until patient can start to develop own Ab |
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Common variable immunodeficiency disease (CVID)
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Onset may occur at any age
Peak occurrences at 1-5 and 15-20 years Decreased serum IgG and IgA levels Normal to low IgM and B cells Patients suffer from Recurrent respiratory and GI infections Autoimmune diseases (SLE, hemolytic anemia, thrombocytopenia) increased risk of lymphoma and gastric cancer |
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CVID
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Defect may be due to
Inability of B cells to proliferate in response to Ag Production of IgM without class-switching to IgG or IgA Treatment: Ig infusion |
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Selective IgA deficiency
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Common (1 in 800 births)
Increased infections in mucosal areas Respiratory, GI, urogenital infections Disease mechanism is unknown Decreased release of IgA from plasma cells? Both autosomal dominant or recessive patterns of inheritance Treatment: antibiotic prophylaxis |
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T cell deficiencies
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~10% of all immunodeficiencies
Patients are susceptible to Fungal, viral and protozoan infections Since T cells also help in antibody response, there also are defects in Ab production |
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DiGeorge syndrome (thymic hypoplasia)
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Due to defective migration of neural crest cells during embryonic development
Facial and cardiac abnormalities Little or no thymus and parathyroid formation Result of a deletion in chromosome 22 Affects both males and females Some correlation with maternal alcohol consumption |
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Characteristics of syndrome
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Few to no mature T cells in blood, lymph nodes or spleen
Recurrent or chronic infections Absent delayed type hypersensitivity reaction B cells may be normal, but fail to mount an Ab response Tx= thymus transplant |
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Functional T cell deficiency
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T cells are normal, but function is impaired
Autosomal recessive defect Patients suffer from Opportunistic infections Increased frequency of autoimmune diseases |
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Chronic mucocutaneous candidiasis
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Patients (mostly children) suffer from recurrent skin and mucous membrane infections with Candida albicans
T cell response to other Ag is normal |
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SCID (severe combined immunodeficiency)
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Most extreme form of immunodeficiency
Both cell-mediated (T cell) and humoral (B cell) immunity is deficient “Combined” Death occurs within ~1 year without aggressive therapy “Boy in the plastic bubble” syndrome Only definitive treatment is bone marrow transplant |
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Diagnosis of SCID should be considered if
patient has |
Unusual or recurrent infection
Failure to thrive and anemia Unusual rashes Family history of neonatal death or consanguinity Total lymphocyte count < 1000/μL |
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If SCID is suspected and HIV infection has
been ruled out |
Avoid live vaccines, including BCG, measles, mumps, rubella, and polio
use Ab prophalyxis against opportunistic infection Pneumocystis carinii (pneumonia) |
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Pathogenesis and characteristics of SCID
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Extreme wasting
Failure to thrive, reduced weight gain in newborn Atrophic thymus Defects in lymphoid stem cells Decrease in B and T cells, Ig and NK cells |
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Heterogeneous group of disorders
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T-B+
Absent T cells, normal or non-functioning B cells T-B- Absence of both T and B cells T+B+ Non-functioning T and B cells Occurs in 1 in 10^5 births |
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Gene therapy
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Used successfully in a few patients with γ-chain deficiency, a type of X-linked SCID
Stem cells are transfected with the γ chain gene resulting in large numbers of normal daughter cells which are re-infused into patient Transfected cells proliferate in response to cytokines and replace defective cells |
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Wiskott-Aldrich syndrome
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Multi-system disorder
X-linked inheritance Mutation in gene which encodes for a protein that binds to various adapter molecules and cytoskeletal components in hematopoietic cells Platelets and WBCs are small and fail to develop and migrate normally |
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Characteristics and pathogenesis
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Bleeding due to thrombocytopenia
Recurrent bacterial infections Allergic reactions Eczema, hyper IgE, food allergies Unable to respond to polysaccharide Ag Antibody levels Normal IgG decreased IgM increased IgE and IgA |
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Treatment
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Bone marrow transplant
Antibiotic prophylaxis Without treatment, life expectancy is ~3 years With increased life expectancy Increased incidence of malignancy |
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Ataxia telangiectasia
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Multisystem genetic disorder leading to neurological deficits, immunodeficiencies and tumors
Ataxia (staggering gait) Telangiectasia (abnormal vascular dilation) Autosomal recessive inheritance Mutation in gene whose product is involved in DNA repair |
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Characteristics and pathogenesis
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Chronic respiratory infections leading to pulmonary damage
Lymphopenia Thymic hypoplasia Decreased IgA, IgE, IgG Increased risk for multiple autoimmune diseases and malignancies (leukemias and lymphomas) |
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Bare lymphocyte syndrome
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Failure to express class II MHC molecules
Due to mutations in genes that induce class II MHC expression Recognition of class II molecules is necessary for CD4 cell activation Results in decreased numbers of CD4+ T cells |
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Diagnosis of immunodeficiencies
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Chronic or recurrent bacterial respiratory infections at any age
IgG, IgA and IgM levels Atypical viral, protozoan or mycobacterial infections T cell counts HIV testing Genetic testing once a preliminary diagnosis has been made |
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Treatment
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Goal is to prevent infection
Mild deficiency Antibiotic prophylaxis Ab deficiency Immunoglobulin replacement therapy T cell deficiency Bone marrow transplant Gene therapy |
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Criteria for successful gene therapy
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The genetic mutation for each patient must be identified and there must be evidence that correcting the mutation will improve the condition
May not correct a dominant mutation The inserted gene must be regulated appropriately |
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The gene must be delivered to the cell safely
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The gene must be delivered to the cell safely
Viruses are often used to deliver the genes Healthy humans contain many harmless retroviruses that may recombine with the viral vector producing a new virus that may cause disease Gene therapy must not cause malignancy If a gene with an active promoter is inserted next to an oncogene, the oncogene may become active and cause cancer |
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Secondary deficiency
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Consequence of other diseases/conditions
Most common cause worldwide Malnutrition Common causes in developed countries Stress Immunosuppressive therapy Cytotoxic drugs Kidney disease (protein, immunoglobulin loss) Infections (malaria) HIV/AIDS |
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Nutrition
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Zinc and magnesium deficiency
Impairs cell-mediated immunity TH1 pattern cytokine secretion Continued poor nutrition Results in loss of fat cells Fat cells normally secrete leptin which has stimulatory effects on the immune system |
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Immune system in first year of life
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Neonates have high numbers of T cells
T cells are all naïve and respond poorly to Ag fetal Ab synthesis begins at 20 weeks adult levels of IgG reached at 5 years Infants rely on maternal Ab Estrogen results in increased production of Ig Breast milk is additional source Bottle fed infants are 60 times more likely to develop pneumonia |
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Aging immune system
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Elderly suffer more infections than the young
Thymic function declines early in adulthood T cells experience replicative senescence Stepwise shortening of teleomeric DNA Occurs after ~40 cell divisions |
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HIV and AIDS
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First described in the early 1980s
Earliest evidence comes from samples from African patients obtained in the1950s Virus first infected humans by jumping from other primate species (chimpanzee) Characterized by severe reduction in CD4+ T cells Severe opportunistic infections (candidiasis) Aggressive forms of Kaposi’s sarcoma or B cell lymphomas |
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Disease of pandemic proportions
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WHO estimates 34 million people are living with HIV/AIDS in 2010
22.9 million in sub-Saharan Africa 2.7 million newly infected in 2010 390,000 are children 1.8 million deaths in 2010 |
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HIV transmission
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sexual contact
blood and blood products Contaminated needles and syringes mother to child In utero During childbirth ? via breast milk |
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HIV: a retrovirus
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RNA virus (2 strands of RNA)
RNA nucleoprotein core (nucleocapsid) Surrounded by a lipid envelop derived from host cell membrane Viral encoded envelope proteins Uses an RNA genome to synthesize a DNA intermediate Backwards or “retro” from most biological entities |
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Protease is used to cleave
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Protease is used to cleave the gp41 and gp120
envelope glycoproteins from a larger precursor. Reverse transcriptase and integrase are required for viral replication |
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Life cycle of HIV
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Infection of cells
Production of viral DNA and its integration into host genome Expression of viral genes Production of viral proteins |
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HIV infects CD4 cells
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binds gp120 cell to infect cell
glycoprotein to host cell CD4 and chemokine receptors (CXCR4 and CCR5) CD4 found on T cells Macrophages Dendritic cells Gp 41 mediates fusion of viral envelope and plasma membrane of host cell Viral genome and proteins enter cell |
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Macrophages and dendritic cells
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Macrophages and dendritic cells are the first to become infected with HIV variant
Have CCR5 coreceptors Macrophage-tropic variant Virus produced by macrophages start to infect CD4 T cells CXCR4 co-receptor Lymphocyte-tropic variant |
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Viral phenotype switches
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Viral phenotype switches to lymphocyte-tropic variant late in infection
Rapid decline in CD4 T cell count Progression to AIDS Lymphocyte-tropic viruses cause the disease Macrophage-tropic variants allow the disease to spread to others |
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Virus is uncoated
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Virus is uncoated by viral protease
RNA is released DNA copy of viral RNA is synthesized Reverse transcriptase enzyme DNA integrates into host genome provirus=integrated viral DNA |
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If infected cell is stimulated
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If infected cell is stimulated (microbe) the cell becomes activated and starts to secrete cytokines
This activation also activates provirus Results in production of viral RNA and proteins |
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Virus forms
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Virus forms a core structure
Migrates to cell membrane Acquires a lipid envelope from the host Is shed as an infectious particle Infects another cell |
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Pathogenesis of disease caused by HIV
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Primary infection of cells in blood and mucosa
CD4 T cells and dendritic cells Infection becomes established in lymphoid tissue (lymph nodes and spleen) Acute HIV syndrome infection spread throughout body via blood stream |
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Immune response
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Immune response
Partial control of viral replication Production of anti-HIV Abs and HIV-specific CTLs |
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HIV --> AIDS
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Clinical latency
Establishment of chronic infection Virus trapped in lymphoid tissue by dendritic cells Low levels of virus production AIDS Other microbial infections result in cytokine release Increased viral replication Destruction of lymphoid tissue and depletion of CD4 T cells |
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Phases of disease
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Acute phase
Asymptomatic phase – clinical latency Symptomatic phase Advanced stage - AIDS |
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Acute phase
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2-4 weeks after infection
50-70% experience mono-like syndrome Lymphadenopathy, fever, flu-like illness Symptoms last 1-2 weeks Virus multiplies in lymph nodes near portal of entry New viral particles are released into bloodstream extremely contagious |
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Asymptomatic phase
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Can last from 2-15 years
Circulating virus has been cleared from bloodstream due to host immune response Both cell-mediated and humoral responses proviral DNA is inserted into genome of CD4 cells Gradual decline of the immune system |
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Symptomatic phase
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Occurs once CD4 T cell count < 500/mm3
Cubic millimeter Effects all organ systems Characterized by Chronic fatigue, persistent low grade fever and diarrhea, night sweats, unexplained weight loss, allergic reactions, severe infections |
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Advanced stage: AIDS
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CD4 T cell count < 200/mm3
Severe and aggressive infections Opportunistic infections malignancies 70% of patients experience CNS changes Dementia Increased viral load in bloodstream |
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Laboratory diagnosis
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Seroconversion occurs 4-12 weeks after infection
Prior to this time, no antibodies can be detected in the serum HIV screening tests are negative at this time, since they detect Ab against the virus |
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Testing methods
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ELISA/EIA
Screening tests Western blot Confirmatory test Viral load assays Monitors disease progression |
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EIA
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HIV Ag are coated onto microtiter wells or beads
Patient serum is added and incubated Wash to remove unbound Ab Add anti-IgG bound to enzyme Wash to remove unbound anti-IgG Add enzyme substrate Measure color development of enzyme-substrate reaction |
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Testing can be performed in
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Testing can be performed in solid or liquid phase
Tubes, beads, microtiter trays, membranes All positive results are repeated to assure reactivity All repeat positive EIA specimens are confirmed by western blot analysis |
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Western blot
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Purified viral proteins are electrophoresed
Proteins are transferred to nitrocellulose membranes Patient serum is incubated with membrane Wash to remove unbound Ab Add anti-IgG bound to enzyme Wash to remove unbound anti-IgG Add enzyme substrate patterns of Ag-Ab reactions are compared to known infected sera |
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Serum is positive
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Serum is positive if
2 of the 3 following bands are detected: p 24 gp41 gp120 Patient is considered positive if both EIA and western blot is positive |
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Viral load assays
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used to monitor dz progression along with CD4 cell counts
Predictor of survival When to initiate anti-viral therapy Monitor anti-viral therapy Current available methods RT-PCR Branched DNA NASBA (nucleic acid sequence-based amplification) |
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Many factors affect CD4 counts
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Many factors affect CD4 counts, especially endogenous
corticosteroids. Therefore counts should always be done at the same time of day, avoiding times of acute illness. |
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Types of drugs
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Reverse transcriptase inhibitors
protease inhibitors Drugs are extremely toxic Must balance effectiveness with tolerance to drugs and patient compliance |
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RT inhibitors
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Similar in structure to DNA
Once incorporated, RT cannot further extend DNA synthesis Results in inhibition of viral replication Aziothymidine-AZT |
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Protease inhibitors
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Inhibit cleavage of precursor proteins which are to be incorporated into the viral core (p24)
Examples Saquinavir Ritonavir Indinavir |
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Combination drug therapy
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Combination drug therapy reduces HIV viral load to
below detectable levels |
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Current CDC recommendations
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Cocktail of at least 3 drugs
HAART – highly active antiretroviral therapy Given to the following Patients with AIDS symptoms Patients within 6 months of seroconversion Patients with CD4 T cell counts <350/mm^3 |
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Successful vaccine must be able to
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Induce an innate immune response
Produce high titers of neutralizing Ab Induce a strong T cell response Induce mucosal immunity Protect against all subtypes of HIV |
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NEF mutations and low virulence
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Early 1980s, 8 patients in Sydney were infected by contaminated blood from a single donor
5 are still alive 3 have high CD4 counts and undetectable viral loads Viral strain of blood donor and recipients have a deletion of the NEF gene Of interest because it could be used to make a possible attenuated HIV vaccine |
