Chapter 13- Failures of the Body's Defenses Flashcards
Primary immunodeficiency diseases
When there is a failure of immunological function as a result of a defect in one or more genes encoding components of the immune system. There are more than 350 primary immunodeficiencies, but most are very rare and occur in small populations that are geographically or culturally isolated
Secondary immunodeficiency diseases
When there is a failure of immunological function as a result of infection or the use of immunosuppressive drugs, rather than a genetic defect
How do immunologists study the immune system in the laboratory?
They knock out a selected gene and look at the immunodeficiency this causes. For some genes, their deletion from human and mouse genomes leads to similar phenotypes, while for other genes the phenotypes are different between the two species
Carrier
A person who carries one copy of a recessive allele for a hereditary disease that does not show symptoms. The allele can be passed onto future generations
X-linked diseases
Caused by recessive defects in genes on the X chromosome. Because males only have one X chromosome and females have two, the disease occurs in all males who inherit an X chromosome with a defective allele. Females must inherit 2 copies of the defective gene to develop the disease, so only females can serve as healthy carriers
When are dominant immunodeficiencies most commonly seen?
When the defective gene encodes a protein that functions in a dimer or a larger protein complex. In these cases, the incorporation of one defective subunit can reduce or destroy the capacity of the complex to function. Before antibiotics were introduced in the 1950s, any dominant trait causing a severe immunodeficiency would have been eliminated from the population with the death of the first child carrying the mutation
Interferon-γ
The main cytokine that activates macrophages. IFN-γ is important for defending against intravesicular bacteria, like mycobacteria. In the innate immune response, it is secreted by NK cells. In the adaptive immune response, it is secreted by TH1 CD4 T cells and cytotoxic CD8 T cells. When Interferon-γ binds to the Interferon-γ receptor on the surface of the macrophage, it induces changes in gene expression that better equip the macrophage for engulfing and killing bacteria
Interferon-γ structure
IFN-γ is a dimer, composed of IFN-γR1 and IFN-γR2 polypeptides. The dimer associates with JAK1 and JAK2 tyrosine kinases. Functional IFN-γ is also dimeric, and binds to sites on 2 IFN-γR1 polypeptides, which cross-links them to initiate a signaling cascade
Dominant allele
An allele that influences the phenotype in both homozygous and heterozygous individuals. Usually refers to disease-causing alleles that encode proteins with functional defects
Recessive allele
An allele that expresses its phenotype only when a person inherits 2 copies. It may also be expressed if no other copy of the allele is present, as in the X chromosome in males
Recessive mutations of IFN-γR1
People with these mutations produce a mutant chain that doesn’t reach the surface. Therefore, people who have inherited 2 mutant alleles only have IFN-γR2 at the surface, lack IFN-γR1, and can’t respond to IFN-γ. People who are heterozygous for this mutation produce enough wild-type IFN-γR1 chains to assemble enough functional receptors and respond to IFN-γ. Recessive disease is severe and presents at an early age
Dominant mutations of IFN-γR1
A person who is heterozygous for a dominant mutation produces a truncated chain that lacks a signaling domain. This chain can assemble into a dimer and bind IFN-γ but can’t signal, even when it is cross-linked with a dimer that has a normal chain. A small amount of functional receptors composed of all normal chains can be made, but most aren’t functional. Monocytes of patients with a dominant mutation are more responsive to IFN-γ than the monocytes of patients with a recessive mutation, so the disease is less severe and detected at a later age
IFN-γ receptor deficiency
Genetic immunodeficiency caused by a lack or low levels of the IFN-γ receptor on macrophages and monocytes. Dominant and recessive mutations have been observed. The disease is characterized by the inability to clear intracellular bacteria, especially mycobacteria
What are the consequences of antibody deficiencies?
These patients are predisposed to infection by pyogenic (pus-forming) bacteria. Encapsulated bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, are not recognized by the phagocytic receptors of macrophages and neutrophils. Therefore, they escape being immediately detected by the innate immune response. These infections are usually cleared when the bacteria are opsonized by specific antibody and complement, and are killed by phagocytes. However, patients with antibody deficiencies can’t clear the infections without antibiotics
X-linked agammaglobulinemia (XLA)
An immunodeficiency disease due to a defect in Bruton’s tyrosine kinase protein (BTK). Males who inherit a BTK mutation on the X chromosome can’t produce functional B cells. This is because B cells are arrested at the pre-B stage.
Bruton’s tyrosine kinase (BTK) function
Contributes to intracellular signaling from the B-cell receptor, and is necessary for the development and differentiation of pre-B cells. BTK is expressed in monocytes and T cells as well, but the functions of these cells don’t seem to be impacted in people with BTK mutations
How are immunodeficiencies usually detected?
By a history of recurrent infections. The type of infection is usually suggestive of the defect- pus forming bacteria suggests a defect of antibody, complement, or phagocyte function. Recurrent fungal or viral infections indicate dysfunction of T cells
Autosome
Any chromosome that is not a sex chromosome
X-linked agammaglobulinemia (XLA) in females
Females who are heterozygous are healthy, but are considered carriers and pass on XLA to 50% of their sons. During development, cells in females randomly inactivate one X chromosome. Therefore, half of developing B cells in a female carrier are arrested at the pre-B cell stage because those cells inactivated the X chromosome that has a functional copy of BTK. The other half of the developing B cells become functional B cells because they inactivated the X chromosome that has the bad copy of BTK, and therefore use the good copy of the X chromosome
Bronchiectasis
Chronic inflammation of the bronchioles of the lung, which can lead to chronic lung disease and death
Long term effects of B cell deficiencies
Patients with diseases like XLA are able to successfully resist many pathogens, and can be treated with antibiotics when they develop infections. However, successive rounds of infection with pyogenic bacteria and antibiotic treatment may lead to permanent tissue damage caused by the excessive release of proteases from the infecting bacteria and defending phagocytes. May lead to bronchiectasis
Treatment of XLA
Monthly injections of intravenous immunoglobulin- the immunoglobulin contains antibodies against all common pathogens and provides passive immunity against those pathogens
CD40 ligand
CD40 ligand on activated T cells interacts with the CD40 on B cells. This interaction helps to stimulate B cell activation, the development of germinal centers, and isotype switching. Macrophage activation by effector CD4 T cells also depends on the interaction of macrophage CD40 and the CD40 ligand on T cells
X-linked hyper-IgM syndrome (CD40 ligand deficiency)
An X linked condition, so most patients are males. Without CD40 ligand, no specific antibody is made against T cell-dependent antigens and there are no germinal centers in the secondary lymphoid tissues. There are abnormally high levels of circulating IgM and extremely low levels of IgG, IgA, and IgE. Patients are susceptible to infection with pyogenic bacteria and have to receive intravenous immunoglobulin infusions
