Immunodeficiencies

Question 1

What are the two types on immunodeficiencies? (2)

Answer 1

Primary
Acquired

Question 2

What is primary immunodeficiency? (2)

Answer 2

Congenital, born with a mutation that results in an immune defect (genetic)

Question 3

What is acquired immunodeficiencies? (2)

Answer 3

Secondary consequence of other events (severe infection, cancer therapy, malnutrition, AIDS)

Question 4

What is autoimmune or inflammatory disease? (2)

Answer 4

Autoreactivity/imbalance in immune responses due to genetic and environmental factors
Against self molecules

Question 5

Features of primary immunodeficiencies (6)

Answer 5

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

Question 6

How are defective genes isolated? (7)

Answer 6

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)

Question 7

B cell defects in babies (2)

Answer 7

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

Question 8

How is agammaglobulinemia (low Ig levels) detected? (4)

Answer 8

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

Question 9

How is agammaglobulinemia caused? (3)

Answer 9

Bruton’s XLA deficiency

X-linked

Greatly reduced number of B cells, not mature- lack enzyme activity for B cell maturation (mutant tyrosine kinase)

Question 10

Is agammaglobulinemia more prevalent in males or females? (1)

Answer 10

Males

Question 11

What is non Bruton’s-agammaglobulinemia? (2)

Answer 11

Equal in men and women - autosomal defects in signalling needed for B cell maturation

Question 12

Treatment for agammaglobulinemia? (1)

Answer 12

IgG replacement therapy

Question 13

What are hyper IgM syndromes? (4)

Answer 13

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

Question 14

What does lack of IgG and IgA result in? (1)

Answer 14

Results in opportunistic infection eg Pneumocystis carinii

Question 15

Defects of T cell (2)

Answer 15

Often effect B cell responses (also macrophage responses) - as B cells need T cell help
Defects in viral and bacterial immunity

Question 16

Example of defect in T cell (2)

Answer 16

DiGeorge’s syndrome- Failure of thymus development- often deletion in chromosome 22
Can affect T cells and/or cytotoxic cells

Question 17

What is Severe Combined Immunodeficiency Diseases-SCID? (4)

Answer 17

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

Question 18

What is autoimmune lymphoproliferative disease? (2)

Answer 18

Excess proliferation of B and T cells and immature thymocytes- due to defects in apoptotic machinery

Question 19

What is X-linked lymphoproliferative disease? (3)

Answer 19

Excess IFN-gamme leads to excessive Th1 skew and
proliferation of B lymphocytes after EBV infection
Die of EBV infection/lymphoma

Question 20

Example of immunodeficiencies of the innate immune system (3)

Answer 20

Leukocyte Adhesion Deficiency I, II, III

Chronic Granulomatus Disease

Chediak-Higashi Syndrome

Question 21

What is leukocyte adhesion deficiency I, II, III? (2)

Answer 21

Lack mechanisms for migration ie lack an integrin, fucose transporter selectin (mediated migration), integrin activation

Question 22

What is Chronic Granulomatus Disease? (1)

Answer 22

Can not produce superoxide (O2−) for phagosomal killing

Question 23

What is Chediak-Higashi Syndrome? (2)

Answer 23

Defect in organelle fusion- prevents movement and fusion of intracellular of granules (NK cells, neutrophils, cytotoxic T cells are unable to kill)

Question 24

What are autoimmune diseases? (3)

Answer 24

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

Question 25

When does autoimmunity occur? (5)

Answer 25

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)

Question 26

Examples of destructive autoimmunity (2)

Answer 26

Insulin dependent diabetes Multiple Sclerosis

Question 27

What is insulin dependent diabetes? (3)

Answer 27

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)

Question 28

What is multiple sclerosis? (3)

Answer 28

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

Question 29

Examples of autoimmune disease (2)

Answer 29

Grave’s disease- hyperthyroidism Hasimoto’s disease hypothyroidsim

Question 30

What is Grave's disease? (3)

Answer 30

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

Question 31

What is ankylosing spondylitis? (3)

Answer 31

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

Question 32

Example of environmental factors that can cause disease? (3)

Answer 32

Molecular mimicry- Rheumatic Fever Induction of inflammation Hormonal influences

Question 33

What is rheumatic fever? (3)

Answer 33

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)

Question 34

How do hormonal influences affect disease? (2)

Answer 34

Women have a higher prevalence of autoimmune diseases, Thyroid disease often triggered post partum