Immunodeficiencies Flashcards
What are the two types on immunodeficiencies? (2)
Primary
Acquired
What is primary immunodeficiency? (2)
Congenital, born with a mutation that results in an immune defect (genetic)
What is acquired immunodeficiencies? (2)
Secondary consequence of other events (severe infection, cancer therapy, malnutrition, AIDS)
What is autoimmune or inflammatory disease? (2)
Autoreactivity/imbalance in immune responses due to genetic and environmental factors
Against self molecules
Features of primary immunodeficiencies (6)
Often rare
Great way to study immune system of humans via humans not mice
Shows the function of cell types/particular molecules
Symptoms- increase susceptibility to organisms that are usually not pathogenic (opportunistic infections)
Antibody deficiencies– bacterial, enterovirus, muscosal infection (IgA deficiency)
Cell mediated ID, bacterial (intracellular), various fungi, viral infection
Therapy- Ig replacement, enzyme replacement, bone marrow transplant, gene therapy
How are defective genes isolated? (7)
Loss of function identified
Compare monozygotic and dizygotic twins
Genetic linkage analysis, microsatellite analysis (phenotype to genotype)
Much higher incidence in men (X-linked)
High incidence in women (hormonal)
Test with mouse models (knock out and transgenic)
Very large cohort studies (genotype to phenotype)
B cell defects in babies (2)
Individuals often healthy for 7-9 months post partum due to maternal antibody
Susceptible to recurrent bacterial and fungal infection - low levels of IgA leads to mucosal impairment
How is agammaglobulinemia (low Ig levels) detected? (4)
Serum samples added to immunoelectrophoresis plate
Serum components separated by electrophoresis
Rabbit anti-human serum is added to the central trough and diffuses into the plate forming precipitin lines
Modern day: analysis via ELISA, quantify B cell number
How is agammaglobulinemia caused? (3)
Bruton’s XLA deficiency
X-linked
Greatly reduced number of B cells, not mature- lack enzyme activity for B cell maturation (mutant tyrosine kinase)
Is agammaglobulinemia more prevalent in males or females? (1)
Males
What is non Bruton’s-agammaglobulinemia? (2)
Equal in men and women - autosomal defects in signalling needed for B cell maturation
Treatment for agammaglobulinemia? (1)
IgG replacement therapy
What are hyper IgM syndromes? (4)
Patients have high levels of IgM in serum
All have defects in class switching and many have defects in hypermutation
Most common is a defect in CD40L/CD40 (therefore can’t interact with T-helper cells)
That results in class-switching, hypermutation and memory B-cell generation
What does lack of IgG and IgA result in? (1)
Results in opportunistic infection eg Pneumocystis carinii
Defects of T cell (2)
Often effect B cell responses (also macrophage responses) - as B cells need T cell help
Defects in viral and bacterial immunity
Example of defect in T cell (2)
DiGeorge’s syndrome- Failure of thymus development- often deletion in chromosome 22
Can affect T cells and/or cytotoxic cells
What is Severe Combined Immunodeficiency Diseases-SCID? (4)
No effective T or B cell responses (often no NK-cells)
Inevitably fatal unless treated with a BMT/HCT
Many mechanisms effecting lymphocyte development, somatic recombination, nucleotide metabolism
What is autoimmune lymphoproliferative disease? (2)
Excess proliferation of B and T cells and immature thymocytes- due to defects in apoptotic machinery
What is X-linked lymphoproliferative disease? (3)
Excess IFN-gamme leads to excessive Th1 skew and
proliferation of B lymphocytes after EBV infection
Die of EBV infection/lymphoma
Example of immunodeficiencies of the innate immune system (3)
Leukocyte Adhesion Deficiency I, II, III
Chronic Granulomatus Disease
Chediak-Higashi Syndrome
What is leukocyte adhesion deficiency I, II, III? (2)
Lack mechanisms for migration ie lack an integrin, fucose transporter selectin (mediated migration), integrin activation
What is Chronic Granulomatus Disease? (1)
Can not produce superoxide (O2−) for phagosomal killing
What is Chediak-Higashi Syndrome? (2)
Defect in organelle fusion- prevents movement and fusion of intracellular of granules (NK cells, neutrophils, cytotoxic T cells are unable to kill)
What are autoimmune diseases? (3)
Under normal circumstances the host does not mount and immune response to self due to tolerance mechanisms
Central/peripheral tolerance - the elimination/regulation of self reacting T/B cells
Systemic, organ specific, protein specific damage can occur
B and T cells start recognising self cells
When does autoimmunity occur? (5)
Breakdown in tolerance
Major defect in central tolerance gene AIRE, FAS or regulatory cells multiple organs targeted
Trauma releases previously unseen antigens (immune privileged sites)
Molecular mimicry-epitope of microorganism cross-reacts with a self protein. Resulting in the subsequent attack of self
Various genetic factors (some MHCI genes can activate T cell against self antigens) and environmental factors (hormones, and infections)
Examples of destructive autoimmunity (2)
Insulin dependent diabetes
Multiple Sclerosis
What is insulin dependent diabetes? (3)
Beta islet cells damaged by inflammatory macrophages,
B cells and T cells, or beta cells destroyed T cells reactive against insulin/GAD self antigen
(found in islet cells)
What is multiple sclerosis? (3)
Destruction of myelin sheath surrounding nerve axons by T cells
and inflammatory macrophages triggering unknown? Damage, EBV infection, genetic
Environmental Factors could also be a cause
Examples of autoimmune disease (2)
Grave’s disease- hyperthyroidism
Hasimoto’s disease hypothyroidsim
What is Grave’s disease? (3)
Disease-antibodies against thyroid stimulating hormone receptor cause constant activation and over production of thyroxine-weight lose tremor
Rapid heart beat and bulging eyes
Symptom - hyperthyroidism
What is ankylosing spondylitis? (3)
T cells and macrophages target pelvis/lower back tendons and ligaments are eventually replaced by bone
Strong linked to the MHCI gene HLA-B27
Misfolded MHCI, MHCI presenting
mimicry peptide from bacteria target fibrocartilage cells
Example of environmental factors that can cause disease? (3)
Molecular mimicry- Rheumatic Fever
Induction of inflammation
Hormonal influences
What is rheumatic fever? (3)
M antigen from Group A Streptococcus is similar to heart protein
After infection, antibodies bind host myosin resulting in complement deposition and FcR-mediated damage by macrophages
Might cause of diabetes, and MS (via EBV)
How do hormonal influences affect disease? (2)
Women have a higher prevalence of autoimmune diseases,
Thyroid disease often triggered post partum
