Immunodeficiencies (Lec 9) Flashcards
Secondary immunodeficiencies
acquired due to environmental
factors (e.g. immunosuppressive
drugs, infection)
Primary immunodeficiencies
- inherited through genetics
- enhanced susceptibility to infection or autoimmunity from childhood
- Dominant, recessive or X-linked
genetic mutations
Opportunistic infections
microbes that do not affect healthy individuals but infect immunocompromised individuals
SARS-CoV-2 and autoimmune disorders
- it can trigger autoimmune disorders
- infection has been linked to increases in auto-immune antibodies
- thought to be due to antibodies towards SARS-CoV-2 also recognizing self
Epstein–Barr virus (EBV) infection and Multiple Sclerosis (MS)
- EBV infection can trigger development of MS
- exact mechanism is not yet known
Immune Response to HIV
- Immune responses towards HIV rarely eliminates virus due to rapid mutation rate
- results in progression to immunodeficiency
Acquired Immunodeficiency Deficiency Syndrome (AIDS)
- HIV leads to AIDS
- the secondary
immunodeficiency with a high lethality rate without treatment
Life cycle of HIV
- virion binds to T cell
- viral envelope fuses with cell membrane and viral genome enters the cell
- reverse transcriptase copies viral RNA genome into double-stranded cDNA
- viral cDNA enters nucleus and integrates into host DNA
- T cell activation induces some transcription of provirus
- transcript are spliced and early proteins synthesized
- viral RNA transported to cytoplasm
- viral RNA is assembled into virions which bud from cell
HIV and drug/vaccine treatments
Targeting various HIV proteins within the five stages of the viral life cycle allows for prevention of
HIV replication
Anti-Retroviral Therapy (ART)
- standard treatment for HIV/AIDS
- combination of antiretroviral drugs to suppress replication
- typically involves inhibitors of reverse transcriptase and viral
proteases - allows for increased T cell numbers
- only stays under control
with continuous drug treatment - can lead to chronic immune system activation and cause chronic inflammatory diseases
CCR5 Mutation and HIV infection
- Co-receptors allow for improved viral entry into T cells and infection of other cell types that can pass virus to T cells
- CCR5 doesn’t bind with HIV R5 strain and prevents that strain of HIV infection
- Patients with deletion in CCR5 gene are protected
What immunodeficiencies affect immune cell development?
- combined immunodeficiencies
- phagocyte deficiencies
- humoral deficiencies
- T cell tolerance deficiencies
Combined immunodeficiencies (CID)
- arise from disruptions to T cell
function, significantly impairment to T cells or loss of T cells (which also disrupts antibody responses) - group of primary immunodeficiencies characterized by defects in both T cells and B cells
- leads to significantly impaired immune response
Severe Combined Immunodeficiencies (SCID)
- Most extreme form of CIDs
- are 5 main categories of SCIDs that result in loss of T cells or lack of T cell function
5 main categories of SCIDs
1 = defect in mitochondrial adenylate kinase
2 = defect in purine metabolism
3 = defective V(D)J rearrangement
4 = defective cytokine signalling
5 = disrupted pre-TCR or TCR signalling
X-Linked Agammaglobulinemia (XLA)
humoral deficiency causing extremely low immunoglobulin levels and almost no naïve mature B cells
Hyper-IgM Syndrome
- CID that results in high IgM levels
- Lack of CD40L or CD40 results in poor T-dependent antibody responses, lack of germinal
centers, lack of somatic hypermutation and class switching - Lack of CD40L also leads to neutropenia (no neutrophils in the blood)
Enzyme-Linked Immunosorbent Assay (ELISA)
- Method to detect and quantify
the amount of an antibody or antigen present based on amount of colour - Amount of colour dependent on how much substrate is cleaved by enzyme
- have an antigen coated well, add enzyme-conjugated antibody to be measured
- add substrate and measure colour
Complement Deficiencies
- impair antibody responses
- are relatively common
- leads to increased susceptibility to bacterial infections and/or immune-complex diseases
- Deficiency in complement restricting control proteins can lead to autoimmunity
Exocytosis Immunodeficiencies
- impair CD8 T cells
- process primarily involves the release of cytotoxic granules that contain molecules like perforin and granzymes, when there is a defect in the exocytosis of these granules, CD8 T cells lose their ability to effectively kill target cells
- can cause
immunodeficiencies such as,
Familial Hemophagocytic
Lymphohistiocytosis (FHL) syndromes
(APECED) autoimmune polyendocrinopathy with candidiasis and ectodermal
dystrophy
- Lack of AIRE (Autoimmune regulator) protein which mediates the expression of
organ peptides in thymus - without AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus
(IPEX) immune dysregulation,
polyendocrinopathy, enteropathy, X-linked syndrome
Lack of regulatory T cells (Tregs) which inhibit autoreactive Helper T cells
Immunodeficiencies are mostly (and successfully) treated with…
replacement therapies
Types of replacement therapies
- protein replacement: IVIG or infusion of recombinant cytokines/enzymes
- cell replacement: = bone marrow or HSC transplantation
- gene replacement = new therapy
