Primary Immunodeficiency

Question 1

What is the definition of immunodeficiency?

Answer 1

Immunodeficiency is defined as a disease characterised by an absence or failure of any part of the immune system that is cause by a genetic or developmental defect producing defective proteins or glycoproteins.

Question 2

What is primary immunodeficiency?

Answer 2

The immunodeficiency is caused by a failure within the immune system itself.

Question 3

What is secondary immunodeficiency?

Answer 3

The immunodeficiency is caused by something else: such as, infection, drugs, poor nutrition.

Question 4

Overview of the response of the immune system.

Answer 4

• Pluripotent haematopoietic stem cells in the bone marrow differentiate via the myeloid or lymphoid pathway into various immune cells.
• Immune cells migrate from blood circulation into the tissues, using cell adhesion molecules, chemotactic factors and complement proteins that regulate the inflammatory response.
• After entering the tissues, phagocytic cells, part of the innate immune response, engulf pathogens by phagocytosis and destroy them with microbial agents.
• Natural killer (NK) cells deal with intracellular infections (phagocytes, complement and antibodies cannot access pathogens once inside the cell). NK cells recognise virally infected cells and tumour cells in a major histocompatibility complex (MHC) and antibody dependent manner.

Question 5

What is the difference between innate and adaptive immunity?

Answer 5

• Innate immunity is the body’s first line of defence against pathogens, it is non-specific so does not differentiate between different pathogens.
• Adaptive immunity provides back up to the innate response as the second line of defence. It takes longer to develop but has a much quicker secondary response that the initial encounter with a pathogen.

Question 6

What is the definition of immunodeficiency disease?

Answer 6

• An immunodeficiency disease is any inherited or acquired disorder in which some aspects of the host defence are absent or functionally defective.
• Those who are affected by severe immunodeficiency are at risk of opportunistic infections caused by microorganisms that healthy individuals can easily get rid of.

Question 7

What is an opportunistic infection?

Answer 7

An infection that occurs more frequently and severely in individuals with weakened immune systems.

Question 8

Facts about primary immunodeficiencies.

Answer 8

• Permanent
• Rare: 1 in 10,000 births
• Defective component determines, type, severity and treatment
• Many cases of primary immunodeficiencies go undetected because our functionally redundant immune system has evolved to provide back ups for when elements of the main system are disabled.
• The type of organism causing recurrent infection can provide a clue:
• Bacteria - Defects of antibody, complement and phagocytes
• Viral - Defects in T-cells
• Fungal - Defects in T-cells

Question 9

IgA deficiency

Answer 9

• Relatively common disorder
• Caused by the failure of IgA bearing lymphocytes to differentiate into plasma cells
• Many individuals are asymptomatic but those with symptoms have sinopulmonary and gastrointestinal infections who are at risk of developing anti-IgA antibodies when given blood products

Question 10

Reticular dysgenesis

Answer 10

• Rare genetic disorder of the bone marrow resulting in complete absence of granulocytes and decreased number of abnormal lymphocytes.
• There is poor development of the secondary lymphoid organs.
• The most severe form of severe combined immunodeficiency (SCID).
• It is caused by the ability of granulocyte precursors to form granules secondary mitochondrial actelyanate kinase 2 malfunction

Question 11

X - Linked Agammaglobulinemia (XLA)

Answer 11

• 1 in 200,000
• Low survival rate
• B-cell development is arrested at the pre B-cell stage and no mature B-cells or antibodies are formed
• Caused by a defect in the gene encoding the tyrosine kinase (BTK)
• Unable to produce functional B cells in males
• Females are carriers but healthy
• IgG production is greatly reduced:
• Affected boys are initially protected by passive immunity in the first few months of life because IgG antibodies are passed from the mother via placenta
• Individuals with XLA have lots of recurrent infections with pyogenic bacteria
• Cell-mediated immunity is unaffected

Question 12

IFN-Y receptor deficiency

Answer 12

• IFN-Y is the main cytokine that activates macrophages which are important for defence against intravesicular bacteria such as mycobacteria
• When IFN-Y binds to IFN-Y receptor, it causes increased phagocytosis and bacteria killing by activating JAK1 and JAK2 pathways
• Patients with IFN-Y receptor deficiency due to recessive mutations have no R1 polypeptides on the cell surface so cannot respond to IFN-Y, so the disease is severe

Question 13

The impact of recessive and dominant mutations in the IFN-Y receptor on monocyte activation

Answer 13

• Receptors for IFN-Y are composed of a dimer of IFNyR1 and IFNyR2. Two such dimers must be cross-linked to the IFN-Y binding site to the IFNyR1 chain for signalling to be triggered.
• Recessive mutant alleles of IFN-Y produce a mutant chain that does not reach the cell surface. People homozygous for a recessive mutation have only IFNyR2 at the surface, lack IFNyR1 function and cannot respond to IFN-Y. People who are heterozygous produce enough wild-type IFNyR1 to assemble functional receptors for a normal response.
• If a person is heterozygous with a dominant mutation, IFNyR1 gives rise to a chain lacking a signalling domain which can assemble into a dimer and bind IFN-Y but cannot signal even when cross-linked with a normal chain.
  ** In simple terms - Dominant mutation of IFNyR1 cause truncated cytoplasmic tails so they are unable to bind and activate JAK1 signalling but can still bind IFN-Y **
• Because only one mutant allele is needed for a dominant condition, 25% of receptors are normal, so blood monocytes still respond to IFN-Y, but less than healthy people

Question 14

Antibody deficiency leads to recurrent pyogenic bacterial infections

Answer 14

Encapsulated pyogenic bacteria (Haemophilus Influenzae, Streptococcus Pneumoniae, Streptococcus Pyogenes and Staphylococcus Aureus are not recognised by phagocytic receptors so first need to be bound by antibodies and complement before they are destroyed by phagocytes.

Question 15

Primary B-cell deficiency: XLA/Bruton’s Disease

Answer 15

• 1st immunodeficiency identified
• Caused by mutations in the Bruton’s Tyrosine Kinase (BTK) gene
• BTK is important for B cell maturation and development and is thought to provide the signal for pre- to post- B differentiation so mutations prevent maturation beyond the the pre-B cell stage
• People with XLA produce early stage B-cells which fail to mature and the production of IgG is grossly depressed
• B-cells are absent or reduced in the peripheral blood and there are few lymphoid follicles or plasma cells in the lymph nodes.

Question 16

Agammaglobulinemia

Answer 16

• A rare disease where the body is unable to produce immunoglobulins which produces a susceptibility to opportunistic infections due to the failure of humoral antibodies. Cell-mediated immunity is unaffected

Question 17

Treatment of XLA

Answer 17

• Antibiotics
• Intravenous IgG administration (passive immunity) against all common pathogens every 3-4 weeks to maintain adequate concentrations of circulating IgG to prevent tissue damage caused by the excessive release of proteases from the infecting bacteria and defending phagocytes

Question 18

X-linked hyper IgM syndrome

Answer 18

• Caused by mutations in the CD40 ligand
• CD40 ligand on activated T-cells interacts with CD40 on B-cells causing B-cell activation
• X-linked hyper IgM syndrome is a rare disorder characterised by recurrent bacterial infections and abnormally high circulating IgM levels paired with very low/absent IgG, IgA and IgE
• This disease is due to mutations on the CD40L (ligand) on CD4+T (helper) cells so cannot bind (CD40R) receptor on B-cells which results in no class switching or memory cells being generated
• Treated with regular intravenous immunoglobulin infusions and antibiotics also given granulocyte-macrophage-colony stimulating factor (GM-CSF) to overcome neutropenia as macrophage activation also requires macrophage CD40 binding with T cell CD40 ligand so cannot produce GM-CSF needed for neutrophil production

Question 19

IgA deficiency

Answer 19

• Relatively common disorder
• Due to the failure of IgA bearing lymphocytes to differentiate into plasma cells
• Mainly asymptomatic but those who have symptoms have sinopulmonary and gastrointestinal infections
• At risk of developing anti-IgA antibodies when given blood products

Question 20

Diagnosis of immunoglobulin deficiencies

Answer 20

• Quantitative measure of Ig
• Screen serum for natural antibodies
  (Anti-A in a group B person, Anti-B in a group A person, Anti-A, Anti-B and Anti-A,B in a group O person
• Attempt to induce active immunity but not using live vaccines (tetanus)
• Enumerate B cells by immunophenotyping

Question 21

Complement defects impair antibody-mediated immunity

Answer 21

• Complements are used to assist antibodies in clearing pathogens
• Defects in C3 and its activation result in lots of pyogenic infections because C3 acts as an opsonin-enhancing removal of bacteria by phagocytosis; whereas defects in C5 - C9, which are used at the end of the complement pathway to produce the membrane attack complex don’t have much effect other than increased susceptibility to Neisseria as complement mediated lysis is the best way to deal with Neisseria
• Early complement proteins (C1 - C4) in the classical complement pathway are important for producing C4B and C3B which help eliminate immune complexes.
• Deficiencies in C1 - C4 cause an accumulation of immune complexes in the circulated deposition of the complexes in tissue, damaging it, and activating phagocytes which cause inflammation and more damage which is known as immune complex disease

Question 22

What is an opsonin?

Answer 22

An opsonin is the general name for antibodies and complement proteins that coat pathogens, thereby facilitating their phagocytosis by neutrophils or macrophages carrying receptors for the opsonin

Question 23

Deficiencies of phagocytic cells

Answer 23

Phagocytosis by macrophages and neutrophils is the main way of removing pathogens. Any deficiency that affects the phagocytes activity has an important effect on the ability to deal with infections.

Question 24

Chediak-Higashi disease

Answer 24

• Rare autosomal recessive disease, due to various mutations in te CHS disease
• Neutrophils, monocytes and lymphocytes contain giant lysosomal granules which result from increased granule fusion. This results in phagocytes which are defective in chemotaxis, phagocytosis and microbicidal activity and NK cells lack cytotoxic activity
• Individuals with this disease have increased susceptibility to infections but these lysosomal defects affect the melanocytes causing albunism and platelets causing bledding disorders.

Question 25

Leukocyte adhesion deficiency

Answer 25

• Caused by lack of CD18 beta-subunit of beta-2 integrins which includes LFA-1 (lymphocyte-function associated antigen-1)
• Individuals with this defect suffer repeated pyogenic infections because phagocytes cannot bind endothelial cells and migrate to infected tissue.
• Patients have problems with wound healing and delayed separation of the umbilical cord is often the earliest manifestation of this defect.
• Bone marrow transplantation is often the treatment of choice as it restores neutrophil function.

Question 26

Chronic granulomatous disease (CGD)

Answer 26

• An example of a phagocytic cell defect
• A qualitative disorder as opposed to quantitative
• Caused by 1 of 4 mutations in which the monocytes, macrophages and neutrophils cannot produce the reactive oxygen intermediates which are required for intracellular killing of phagocytosed organisms, so cells are able to phagocytose microorganisms but do not destory them. This is because they have defects in NADPH (nicotinamide adenine dinucleotide phosphate) oxidase system which produces hydrogen peroxide.
  Genes responsible for CGD
• X-linked: 70%
• Autosomal recessive: 30%
• Mutations can affect any of the components of the NADPH oxidase system resulting in CGD. The cytochrome b558 component in the membrane is composed of p22phox and gp91phox (phagocyte oxidase) components. 70% of CGD patients have mutations of gp9191phox which is located on the x chromosome. The remaining cases result from mutations in 1 of the other 4 components whose genes are loctaed on the various autosomal chromosomes.
  Characteristics of CGD
• Defective respiratory burst which is the oxidative metabolism which occurs following activation
• Activation of NADP/cytochrome oxidase is measured by superoxide anion production following stimulation of phorbol ester.
• CGD results in recurrent and bacterial infections which if unresolved can lead to granuloma formation that can obstruct the gastrointestinal and urogenital systems
• Limited range of recurrent infections, the most common pathogen is staphylococcus aureus but there is some gram negative bacilli and fungi. The main reason for this is because many bacteria generate hydrogen peroxide through their own metabolic processes and therefore help to destroy themselves. However, catalase positive bacteria will survive because the peroxide will be destroyed. These catalase bacteria will be taken up by neutrophils but cannot be destroyed within the phagocyte.
• Another reason for the lack of diversity of infection is due to the most virulent bacteria, which tend to be resistant to the oxygen-independent microbial mechanisms of the phagocyte.
  Diagnosis
• Stimulation of superoxide production using the phorbol ester
• Nitroblue Tetrazolium test: following phorbol myristate acetate stimulation, reduction of yellow NBT to blue/black formazan occurs in the healthy controls but is completely absent in cells from a patient with X-linked chronic granulomatosus.
• The mother of the patient is a carrier of the mutation andhas both NBT-postive and -negative cell populations
  Treatment
• Prophylactic antibiotics and antifungals which reduce infections
• Interferon gamma is used to stimulate the production of superoxide by CGD neutrophils which means they can kill injested microbes, and so results in considerably fewer infections
• Bone marrow transplantaton because CGD results from a single gene defect

Question 27

What is granuloma?

Answer 27

Chronic inflammatory lesion characterised by large numbers of cells of various types, some degrading and some repairing the tissue.

Question 28

Severe Combined Immunideficiency (SCID)

Answer 28

• Severe immunodeficiency
• Affects 1 in 80,000 live births
• Classed as severe because of a total failure of T-cell development, resulting in defective cell-mediated and humoral immunity
• Most will die during their first year unless given a haematopoietic stell cell transplant
• Recurrent viral, bacterial, fungal, protozoan infections due to lymphopenia
• The children have recurrent infections and have prolonged diarrhoea resulting from gastrointestinal infections and pneumonia due to pneumocytis carinii and also have candida albicans growing rampantly on skin and in mouth
• If vaccinated with live attenuated organisms, these individuals usually die of recurrent infections
  Genes and mechanisms
  Treatment
• Haematopoietic stem cell transplant
• Patients with adenosine deaminase deficiency (ADA SCID) without a suitable HSCT match recieve weekly ADA enzyme replacement therapy.
• If B-cells are infected, intravenous immunoglobulins are given every 3-4 weeks
• Gene therapy is the ideal treatment when a matched transplant is not available

Question 29

Primary T-cell deficiency

Answer 29

• Opportunistic infections
• Poor humoral immunity
• Allergies
• Lymphoid malignancies
• Autoimmune diseases (inefficient negative selection in the thymus, failure to generate T regulatory cells)
  Diagnosis
• Hypo or unreactive in skin tests to tuberculin, candida or mumps
• Phytohaemagluttin activation of T-lymphocytes
• Enumeration of T cells by immunophenotyping CD3
  Defective gene - disorder - typical infections
  AIRE - Autoimmune polyendocrine sydrome 1 - Candida albicans
  FOXP3 - Immune dysregulation, polyendocrinopathy enteropathy, X-linked (IPEX) - None

Question 30

DiGeorge Velocardiofacial syndrome

Answer 30

• An example of T-cell deficiency which is a develppmental disorder affecting thymus (failure of the thymus to develop properly from the third and fourth pharyngeal pouches.
• Other features:
• Lack parathyroid: hypoparathyroidism is a term which describes the abnormally low production of parathyroid hormone by the parathyroid glands. Common symptoms are these of low blood calcium, muscle spasms, tetany, facial grimacing, laryngeal spasms and seizures
• Heart abnormalities
• Fish-like mouth
• Down-slanting palpebral fissures
• 1 in 4,000
• Lack of thymus causes:
• Haematopoietic stem cells that cannot differentiate into T cells so no T cells
• The thymus dependent areas in lymphoid tissue are sparsely populated
• Poor developed lymphoid follicles
• No cell-mediated immunity
• Antibodies can be produced but it is subnormal because you need T-cells to help with the B-cell response
  Treatment for total aplasia (lack of development of an organ or tissue)
• Transplantation of cultured, mature thymic epithelial cells has successfully reconstituted the immune function in patients missing their thymus.
• Rare
• Antibody administration
  Partial hypoplasia (incomplete/underdevelopment of an organ/tissue)
• Patients have a partially developed but not completely absent thymus
• More common
• Normal antibody responses
• No immunological intervention needed
  Causes
• Deletion of TBX1 gene - this transcription factor is highly expressed during the phases of embryonic development when the facial structures, heart, thyroid, parathyroid and thymus are forming.
  Confirmation
• Karyotype analysis
• FISH