module 09 section 03 (immunodeficiency) Flashcards
recall: what are immunodeficiency diseases?
a defect in the immune system such that the body cannot effectively fight infections or prevent diseases
recall: what are the two main categories of immune disorders?
(1) 1° imunideficiency: inherited immunodeficiencies
(2) 2° (acquired) immunodeficiency: a result of environmental factors that compromise the immune system
more specifically, what is 1° immunodeficiency caused by?
hereditary or genetic defects that result in tha absence or improper functioning of parts of the body’s immune system
all 1° immunodeficiency disease share what common feature?
causing a defect in one of the body’s immune system functions, by affecting either one or multiple components
generally, how are 1° immunodeficiency diseases classified?
based on which part of the immune system is affected
what are the 5 major classifications of 1° immunodeficiency disease?
(1) humoral immunity (B-cells)
(2) cellular immunity (T-cells)
(3) humoral and cellular immunity (B-cells and T-cells)
(4) phagocytes
(5) complement proteins
with 1° immunodeficiencies, the affected component of the immune system can be:
missing, reduced in number, or abnormal and malfunctioning
what classification of accounts for more than half of 1° immunodeficiencies?
those involving problems with B-cells
what is DiGeorge syndrome?
1° immunodeficiency that results from a depletion of a segment of chromosome 22
DiGeorge syndrome causes developmental ______ in which the ______?
- thymic aplasia
- thymus fails to develop
what does developmental thymic aplasia result in?
the absence of cell-mediated immunity due to the absennce of differentiated/mature T-cells (T-cells mature in the thymus)
the absence of cell-mediated immunity is aka?
anergy - absence of the normal immune response to a particular antigen or allergen
patients with DiGeorge syndrome have an increased susceptibility to?
fungal and viral infections
what is Bruton’s (X-linked) agammaglobulinemia?
aka XLA
inherited immunodeficiency disease caused by mutations in the gene encoding for Bruton tyrosine kinase
what is BTK (bruton tyrosin kinase) responsible for?
what are the implications of this for Bruton’s agammaglobulinemia?
- mediating B-cell development from pre B-cells to mature B-cells through a signalling effect on the B-cell receptor
- individuals with bruton’s agammaglobulinemia do not generate mature B-cells
what is implied by the lack of mature B-cells in Bruton’s agammaglobulinemia?
lack of Igs in the bloodstream
the deficient humoral immune response in individuals with
Bruton’s agammaglobulinemia makes them more prone to what?
serious and fatal bacterial infections
Bruton’s agammaglobulinemia presents clincially similar to what other disease?
hypogammaglobulinemia (CVID), however CVID is not an inherited disorder with known genetic causes
how is XLA typically treated?
is this a cure?
- by intravenous infusion of antibodies
- does not cure but reduces severity of infections due to passive immunity from the exogenous antibodies
historically, XLA was mistaken for what disease?
is this more severe or less severe than XLA?
severe combined immunodeficiency (SCID) - more severe
what is SCID?
- a group of defects from one of many genes that results in a heterogeneous disorder
- it causes a defective antibody response either directly through mature B-cell malfunctioning or indirectly through ineffective T-cell dependent B-cell activation
what is the role of the genes associated with SCID?
proper development of B-cells and T-cells
SCID causes a defective antibody response _____ through _____ or _____ through _____?
- directly through mature B-cell malfunctioning
- indirectly through ineffective T-cell dependent B-cell activation
SCID makes affected individuals highly susceptible to what?
life-threatening infections by viruses, bacteria and fungi
SCID is also known as what? why?
“bubble boy” disease - affected individuals must live in sterile environments due to their vulnerability to infectious diseases
are most SCID cases X-linked? if so why, if not what are they?
yes - due to mutations in the gene that encodes for the common gamma chain found on the X-chromosome
mutations in the SCID gene prevent? due to what?
why?
the development of a fully functional immune system due to:
- low T-cell and NK counts
- non-functional B-cells
- becuase gamma is a characteristic of receptors for IL-2, IL-4, IL-7, IL-9 and IL-15, which are implicated in the development of B and T cells
- if there’s a mutation in this receptor, these cytokines are non-functional and cannot exert their effects in B/T-cell development
what therapeutic modality has potential for treating patients with SCID? why?
gene therapy - because these conditons are caused by defects in an identifiable molecule with a known gene
recall that secondary immunodeficiencies are not genetic but caused by external factors, what are the 4 main causes of secondary immunodeficiency?
- malnutrition
- medication
- aging
- disease
explain malnutrition as a cause of secondary immunodeficiency
is this the most common cause?
- most common cause
- deficeincy in one or more nutrients can result in improper functioning of the immune system
what is the largest global cause of malnutrition?
protein calorie deficiency - where T-cell population decreases in proportion to protein levels, resulting in reduced ability to fight infection
explain medication as a cause of secondary immunodeficiency
-cytotoxic agents (chemo/radiation therapy) target rapidly dividing cells in the body - this can supress immune system
- immunosupressants are used to intenionally supress the IS (organ transplant/AI disease)
- can completely supress IS
- can increase susceptibility to opportunistic infections
explain aging as a cause of secondary immunodeficiency
- recall: thymus shrinks as you age so you’re producing fewer T-cells
- why nutrition is more important in older people - especially calcium and zinc bc their deficiencies are common in the elderly (may be due to reduced ability of intestine to absorb them)
explain disease as a cause of secondary immunodeficiency
- prolonged/chronic disorders can cause secondary immunodeficiency due to stress placed on the immune system
- e.g. diabetes - lymphocytes don’t function optimally in high blood sugar levels
- e.g. bone marrow cancer decreases T/B-cell production
what is HIV? why do we care?
- ss retrovirus that’s transmitted through bodily fluids
- most studied case of secondary immunodeficiency
recall: what is the process of an HIV infection?
- requires fusion of the viral gp120 (envelope protein) to the CD4 receptor on T-cells, which permits HIV entry into the CD4+ T-cell
- then HIV releases reverse transcriptase to convert its RNA into DNA
- then it uses integrase to integrate HIV-DNA into T-cells genetic content in the nucelus
- once integrated, HIV uses host machinery to make HIV proteins for assembly into immature HIV that buds out of the host cell
- following release, HIV results in progressive destruction of helper T-cells
what are the host cell surface receptors used by HIV?
- CD4 = primary receptor for virus
- CCR5 = coreceptor
- CxCR4 = coreceptor
what type of cells does HIV infect?
T-cells
how does HIV viral DNA enter the host DNA?
interactions btwn virus and coreceptor allow virus uncoating, and entry of the viral nucleocapsid containing the viral genome into the cell
what is the latency of an HIV infection?
- after the virus enters the cell, RT copies RNA into ds DNA
- integrase then mediates the integration of viral DNA into host cell chromosomal DNA
- HIV is latent while integrated in host DNA (can persist in the cell in an inactive state)
- reactivation of the virus occurs when the host cell is activated and viral transcription is initiated
explain the creation of a new HIV particle
- after viral transcription, viral mRNA forms thats translated into viral proteins
- genome length transcripts of the virus also accumulate
- these assemble into immature, non-infectious HIV particles at the host cell membrane
- this then buds off
- maturation of this new particle continues after it buds off from the host cell to create a new infectious particle with the same nucleocapsid morphology
- specifically, HIV proteases within the viral particle cleave viral polypeptides which results in mature, infectious viral proteins
what is the effect of HIV on infected cells?
- budding process destroys the membrane of infected cells (cell death)
- apoptosis is also induced in unaffected T-cells by overexpression of antigenic ligands (incl. gp120)
- i.e., severly reduced number of CD4+ T-cells even though there’s a low number of infected T-cells
the loss of CD4+ helper T-cells if central to the development of?
AIDS
the loss of CD4+ helper T-cells contributes to abnormal production of?
what does this lead to?
- IL-1 and TNF-a
- leads to decreased proliferation in response to antigens
- leads to decreased delaying hypersensitivity and cell-mediated immunity to viral, fungal and parasitic infections
- addional infections further inhibit the immune response
what are other immunological abnormalities associated with HIV? (5)
(other than low CD4+)
- abnormal macrophage function (related to IL-1)
- decreased NK cell activity
- decreased CD8+ cytotoxic T-cells later in infection
- increased non-specific Igs
- increased auto-antibodies
summarize the progression of an HIV infection
- begins with mil flu-like symptoms
- some may be asymptomatic (however theyre still infectious)
- generalized lyphadenopathy is associated with early stages (enlargment of 2+ non-contagious lymph node groups)
- slowly, immune function gets worse and the following may present:
- pneumocytis carinii
- kaposi’s sarcoma
- non-hodgkin lymphoma
- candidiasis
- cytomegalovirus
- dementia
- death
what are idiopathic immunodeficiency diseases?
those that have no known cause
idiopathic immunodeficiency diseases are often?
B-cell immunodeficiencies
what are the 2 most common idiopathic immunodeficiency diseases?
(1) common variable hypogammaglobulinemia
- affects 1 in 70,000 btwn age 15-35
- mostly defects in the antibody variable region
(2) selective IgA deficiency:
- affects 1 in 700
- can’t be treated with gamma globulins bc foreign IgA elicits an immune response
