Lecture 31: Immunodeficiency Flashcards
primary immunodeficiency is aka ___
inborn error of immunity
what causes primary immunodeficiency?
genetic defect that nagatively impacts immune function
secondary immunodeficiency is aka ____
acquired immunodeficiency
what is secondary immunodeficiency?
a loss of immune function due to exposure to an external agent such as certain infectious agents or medical treatments
in primary immunodeficiency, depending on what factors, the oucomes can range from unnoticeable to fatal?
the nature of the mutation (homozygous/heterozygous, deletion/mutation/loss of fx)
in primary immunodeficiency, depending on the affected component of the immune system, there will be increased ____ or ____
susceptibility to infection by pathogens OR sensitivity to autoimmune/hypersensitivities
primary immunodeficiencies are categorized by the types of cell involved in the _____ stage at which the defect occurs
developmental
severe forms of primary immunodeficiency appear at what stage in life? Why do they occur?
early in life as a result of recurrent infections and associated health problems
reflexive testing for every newborn in nova scotia is screened for ___
SCID
how is the testing done for newborns to see if they have SCID?
testing by qPCR identifies if TCR and BCR have been rearranged (indicating normal T/B development)
what are 10 warning signs for primary immunodeficiency in children?
- 4/more ear infections in 1 year
- 2/more serious sinus infections in 1 year
- 2/more months of antibiotics w/ little effect
- failure to gain weight
- recurrent deep skin or organ abscesses
- 2/ more pneumonia infections in 1 year
- persistent thrush in mouth or fungal infection on skin
- need for IV antibiotics to clear infections
- 2/more deep-seated infections including septicemia
- family hx
lymphoid immunodeficiencies may involve what types of cells?
B cells, T cells, both B & T cells, sometimes NK cells
lymphoid immunodeficiencies mainly affect the ____ immune response
adaptive
the B cell defects in lymphoid immunodeficiencies range from _____ to ____
a complete loss of B cells and immunoglobin to a selective loss of certain immunoglobulin classes such as IgA
T cell defects in lymphoid immunodeficiencies range from ____ to ____
total absence of T cells to loss of particular functions, such as specific cytokine production or loss of costimulatory molecules
in lymphoid immunodeficiencies, ____ immunity to T-dependent antigens is also affected
humoral
in lymphoid immunodeficiencies, T cell dysfunction together with some impact on antigen function is called _____
combined immunodeficiency
can the same dx be caused by more than one gene alteration?
yes
what is SCID?
severe combined immunodeficiency
what is BLS?
Bare-lymphocyte syndrome” MHC deficiency
what is the specific defect that leads to DiGeorge syndrome?
thymic aplasia
DiGeorge syndrome causes what immune defect?
decreased T cell count
Hyper-IgM syndrome is caused by defective _____ or ____
CD40 ligand ot CD40
what immune fx are impaired by Hyper-IgM syndrome?
elevated IgM due to loss of other isotypes, defective APC leading to reduced T cell responses to intracellular pathogens
severe combined immunodeficiency (SCID) refers to a family of disorders that affects all leukocyte differentiation, or specifically impairs T, B and/or NK cells through one of what 3 ways?
- activation defects
- defective VDJ rearrangement
- defective cytokine signalling
t/f SCID can result from an array of mutations and therefore exists as dx subtypes
t
what are 5 subtypes of SCD?
- reticular dysgenesis
- adenosine deaminase (ADA) deficiency
- RAG deficiency
- JAK-3 kinase or common y-cahin deficiency
- CD3 zeta chain deficiency
what is the the defect in the reticular dysgenesis subtype of SCID?
mitochondrial adenylate kinase
what is the pathology of the reticular dysgenesis subtype of SCID?
a defect in mitchondrial adenylate kinase prevents hematapoietic stem cell differentiation into myeloid and lymphoid progenitor cells, leading to total lack of leaukocytes
_____ is a rare form of SCID that is lethal if the patient does not get aggressive treatment using bone marrow transplantation
reticular dysgenesis
what is the treatment of reticular dysgenesis?
bone marrow transplantation
what is the pathology of adenosine deaminase deficiency?
results in the accumulation of adenosine (whoch is normally converted to inosine by ADA), which is toxic to T, B and NK cells
what is the pathology of RAG deficiency?
a defect in the genes coding for the recombinase enzymes (RAG-1 and RAG-2) required for TCR and immunoglobulin gene rearrangement (results in failure of T and B cell precursors to differentiate)
what is the pathology of JAK-3 kinase or common y-chain deficiency?
impeded signalling through cytokine receptors (IL-2, IL-15_ that are critical for T cell and NK cell development and action
what is the pathology of CD3 zeta chain deficiency?
disrupts TCR signalling which impacts T cell development leading to low # or no mature T cells
what are the sx characteristics of SCID?
severe and recurrent infections (bacterial, viral, fungal) that usually lead to death early in life
what is the effect of live or attenuated vaccines on people with SCID?
can be fatal
how can the life of SCID patients be prolonged?
confinement in a sterile environment
what is the current treatment for SCID?
bone marrow transplantation from HLA-matched donor
if the bone marrow transplant works, will a patient be cured of SCID?
yes
what is a potential alternative treatment to bone marrow transplantation to treat some forms of SCID (ex; ADA deficiency), but is only in experimental stages?
gene therapy
what is Bare-lymphocyte syndrome?
defective expression of MHC 1 or 2
In what way does Bare-lymphocyte syndrome resemble SCID?
T and B cell activation is sevrely impaired in both
an MHC1 deficiency results from a defect in genes coding for _____ or ____ resulting in a deficiency in __Tcells and depressed cellular immunity
B2-microglobulin or TAP; CD8+ T cell
MHC 2 deficiency results from a failure to transcribe genes that encode ____ molecules, resulting in impaired selection of ____T cells in the thymus and limited _____cell responses that impact cellular and humoral immunity
MHC2; CD4+ T cells; helper T cell
T cell deficiencies can be the result of developmental defects in the ____ or mutation of proteins involved in the _____
thymus; TCR signalling
DiGeorge syndrome is aka ___
congenital thymic aplasia
in DiGeorge syndrome, children are born without a ___ or ____
thymus or parathyroids (some thymic tissue typically present)
in DiGeorge syndrome ____immunity is impaired and B cells cannot _____
cell-mediated; B cells cant make specific antibody in response to infection or vaccination
what is the effect of viral, fungal or protozoal infections on patients with DiGeorge syndrome?
often fatal
what is a potential treatment for DiGeorge syndrome?
a fetal thymus transplant can provide hormones and allow T cell maturation
X-linked Hyper-IgM syndrome is an inherited deficiency in ____ on T cells or ____ on B cells
CD40L on T cells and CD40 on B cells
what is the role of APC in hyper-IgM syndrome?
prevents B cell responses to T-dependent antigens
what causes the high IgM in Hyper-IgM syndrome?
since B cells cant respond to T cells, but can respond to T-independent antigens, this causes the disproportionate production of IgM
how are DC impacted by hyper-IgM syndrome?
DC maturation, IL-12 secretion and licensing for CD8+ T cell activation is impaired bc DC also depend on the CD40/CD40L signalling of helper T cells
X-linked agammaglobulinemia occurs very rarely in which sex?
males (bc it is an X-linked disorder)
X-linked agammaglobulinemia is caused by a defect in _____
Bruton’s tyrosine kinase
what is the fx of bruton’s tyrosine kinase?
required for the pro-B cell to pre-B cell transition
people with X-linked agammaglobulinemia lack what types of cells?
mature B cells and circulatinf antibody (bc maturation is halted)
what type of infections are common in X-linked agammaglobulinemia?
recurrent bacterial infections (especially by encapsulated bacteria)
how can X-linked agammaglobulinemia be treated?
with antibiotics & injections of purified pooled human IgG
when treated with IgG for X-linked agammaglobulinemia, what types of infections still happen? why?
sinopulmonary infections due to continued lack of secretory IgA
what are selective immunoglobulin deficiencies?
result when one antibody class or subclass is missing
what is the most common type of selective immunoglobulin deficiency?
IgA
IgA deficiency is characterized by ____
a failure of IgA-committed B cells to differentiate into plasma cells
what are the characteristic sx of a patient with IgA deficiency?
frequent bacterial and viral sinopulmonary infections and increased allergies due to excessive IgE production
what is the treatment for IgA deficiencies?
braod-spectrum antibiotics
chronic granulomatous dx and leukocyte adhesion deficiencies are both examples of defects in ___ cell fx
innate immune cell
what is the defect that causes chronic granuloatous?
mutations in phagosome NADPH oxidase subunits
what immune fx are impaired by chronic granulomatous?
no ROS or RNS for killing of phagocytosed pathogens
what is the defect that causes leukocyte adhesion deficiencies?
defective integrins
what immune fx are impaired by leukocyte adhesion deficiencies?
leokocyte extravasation and chemotaxis
t/f defects in TCR signalling can be fatal if untreated
t
myeloid cell immunodeficiencies affect ____ immune fx
innate
what is the defect that causes chronic granulomatous dx?
defect in the oxidative pathway that phagocytes use to make reactive O2 and n2
what is the impact of chronic granulomatous dx on phagocytes?
phagocytes are unable to kill many types of phagocytosed bacteria
chronic granulomatous dx results in excessive ____ responses
inflammatory
what is the effect of chronic granulomatous on antigen processing and presentation?
impaired
people with chronic granulomatous have higher incidence of what types of infections?
bacterial and fungal
chronic granulomatous is a ____ type immunodeficiency
myeloid
leukocyte adhesion deficiency (LAD) is a ____ type immunodeficiency
myeloid
how does lymphoid adhesion deficiency (LAD) occur?
failure to express the B subunit (CD18) of the adhesion molecules LFA-1, MAC-1 (CR3) and gp150,90(CR4)
what is the impact of LAD on extravasation of neutrophils, monocytes, and lymphocytes?
impaired
what is the effect of LAD on CTL and NK cells?
impairs their ability to adhere to target cells
what is the impact of LAB on T helper cells and B cells?
failure for these cells to form conjugates
what are some of the common sx of a patient with leukocyte adhesion deficiency?
frequent bacterial infections and impaired wound healing which may lead to premature death
complement deficiencies are relatively ____ (common/rare)
common
in complement deficiencies, the severity is linked to the_____
specific component (s) involved
deficiencies in any of the early components of the classical complement pathway (such as ___, ___, ___, __ & ___) prevents the generation of ____
Clq, Clr, C1s, C2 and C4 ; C3 convertase
when deficiencies happen early in the classical complement pathway and C3b (opsonin) is not made, what is the impact?
leads to bacterial infections and immune complex dx due to a failure to clear immune complexes by phagocytosis
what is the severity level of C3 deficiencies?
severe
C3 deficiencies result in frequent ____ type infections and ____ dx
bacterial; immune complex
why does a C3 deficiency result in frequent bacterial infections?
no opsonization by C3b and failure to form membrane attack complex
why can C3 deficiencies lead to immune complex dx?
immune complex clearance by phagocytes is impaired
deficiencies in which complement proteins cause few health problems except for an increased rate of infections by Neisseria species?
C5-C9 deficiencies
why are Neisseria species infections able to infect better when there is a C5-C-9 deficiency?
the Neisseria species are typically susceptible to lysis by the membrane attack complex
what is an example of an infection that causes secondary/acquired immunodeficiency?
HIV
what are 4 causes of secondary/acquired immunodeficiency?
- infections
- Agent-Induced immunotherapy
- Age
- Malnutrition
what are 3 examples of agent-induced immunotherapy?
- chemotherapy
- radiation
- immunosuppression (i.e. corticosteroids)
what age-related populations are more at risk for age-related secondary immunodeficiency?
very young and very old
what are 2 forms of malnutrition that can lead to secondary / acquired immunodeficiencies?
- prolonged aproteinemia
2. macronutrient insufficiency (Vitamin D, C, zinc …. are these MACRO nutrients or micronutrients??)
what is AIDS?
acquired immunodeficiency syndrome
AIDS results from progressive loss of immune responsiveness due to infection & loss of ____ cells by _____ retrovirus
CD4+ T helper cells; human immundeficiency virus-1 (HIV-1)
AIDS is defined as having a T cell cout lower than ___T cells/u blood OR presence of ____
200; AIDS defining illness
t/f macrophages and DC are affected by HIV-1
yes
how can AIDS result in death?
due to opportunistic pulmonary inections, rare cancers and central nervous system complications
how can HIV-1 be transmitted?
sex, blood, mother to infant (blood transfer during birth and or milk during breastfeeding)
does the same strain of HIV-1 infect naive T cells and Tcm vs macrophages, DC and Tem cells?
no, its different strains
what act as co-receptors for HIV-1?
CD4 and chemokine receptors (CCR5 and CXCR4)
initial HIV infection is by ____variants and ___ variants arise later
R5; X4
HIV-1 infected macrophages and DC act as ____
viral reservoirs
HIV-1 infected T helper cells eventually die as a result of _____
viral replication
____ therapy inhibits HIV replication and dx progression
antiretrovial
2 HIV patients were given cell transpants with ___ and now appear to be clear of HIV
CCR5 delta delta (a CCR5 mutant)
an example of a chemotherapeutic drug that can cause agent-induced and other secondary immunosuppressive immunodeficiencies
cisplatin
chemotherapeutic cells inadvertently target bone marrow stem cells, T & B cells, resulting in ____ and ____
leukopenia (esp. neutropenia) and loss of immune fx
____ is an immunosuppressive drug used to prevent oragn graft rejection, but also interferes with normal T cell responses
cyclosporin A
what is the effect on the immune system & risks of taking cyclosporin A?
T cells are present, but non-responsive, resulting in overwhelming infections and increased risk of cartain cancers, exp lymphomas
