Sara- Primary Immunodeficiency Flashcards
What cause primary immunodeficiencies?
Inherited defects in genes for components of the immune system
What are primary immunodeficiencies
Diseases usually revealed in early childhood due to enhanced susceptibility to infection
What are secondary immunodeficiencies?
(2)
Diseases caused by environmental factors
e.g. caused by infections or immunosuppressive drugs
Give an example of a primary immunodeficiency
X-Linked agammaglobulinemia
Give an example of a secondary immunodeficiency
Acquired Immunodeficiency Syndrome (AIDS) -> caused by HIV
List the causes of secondary immunodeficiency
(7)
Malnutrition
Diseases e.g. HIV
Genetic and metabolic diseases
Immunosuppressive drugs
Surgery and trauma splenectomy
Age extremes: prematurity and old age
Environmental stress
How does malnutrition cause secondary immunodeficiency
Clinical obesity has negative effects on natural killer cells
Lack of NK activity -> increased viral infections and cancer in clinically obese
Give an example of an environmental stress that causes secondary immunodeficiency
Cigarette smoking
How can surgery and trauma cause secondary immunodeficiency?
(3)
Splenectomy
B cell populations lost
Knock on effects
What are the ten warning signs of primary immunodeficiency (will come up on the exam)
Four or more new ear infections within one year
Two or more serious sinus infections within one year
Two or more months on antibiotics with little effect
Two or more pneumonias within one year
Failure of an infant to gain weight or grow normally
Recurrent, deep skin or organ abscesses
Persistent thrush in mouth or fungal infections on skin
Need for intravenous antibiotics to clear infections
Two or more deep-seated infections including speticemia
A family history of primary immunodeficiency
How have primary immunodeficiencies facilitated our understanding of how the immune system functions?
By highlighting the effects of the absences of particular proteins
What causes most PIDs
Caused by mutant genes that confer no selective advantage to the individuals that carry them
They vary in severity from mild to fatal if the defect is not corrected or the infections are not prevented
List the different categories of primary immunodeficiency
(6)
Antibody deficiencies
Combined cellular and antibody deficiencies
Cellular deficiencies
Phagocytic cell deficiencies
Complement deficiencies
Very rare -> immune regulation deficiency (AIRE defect)
What are CIDs
Combined Immunodeficiencies
Write a note on combined immunodeficiencies
(3)
Among the most severe PIDs
Result from an absence of T cells, or impaired T cell function, combined with some disruption of antibody response
No T helper cells needed for B cell activation -> no antibody production
What causes CID
(3)
Absence of T cells
Impaired T cell function
Combined with some disruption of antibody response
What does a T cell deficiency do?
(3)
Results in no B cell activation
Results in no antibody class switching
Reduction in cell mediated cytotoxicity, therefore an increase in viral, protozoal, fungal and mycobacterial infections is observed
Write about SCID
The most extreme forms of CID
What gene defects can cause CID?
(5)
CD3 chains
Mitochondrial adenylate kinase
RAG1 and RAG2 or Artemis
Common y chain and JAK3
Adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP)
What do defects in adenosine deaminase or purine nucleoside phosphorylase do?
(3)
Nucleotide metabolites accumulate
These are particularly toxic to developing T cells and less so to developing B cells
Autosomally inherited
What does ADA stand for?
Adenosine deaminase
What does PNP stand for?
Purine nucleoside phosphorylase
Write about common y chain and JAK3 and how they cause SCID
Common y chain is X linked
JAK3 is autosomally inherited
Lack of signalling or signal transduction
Write about RAD1 and RAG2 or Artemis
No T cell receptors
No Antibody production
Write about CD3 chains and how they cause SCID
No T cell receptor complex expression for signalling
Write about mitochondrial adenylate kinase and how they cause SCID
Defective differentiation of myeloid and lymphoid lineages from stem cells
Reticular dysgenesis
What are antibody deficiencies?
A diverse spectrum of diseases
Ranges from the complete absence of mature recirculating B cells, plasma cells and Abs to the selective absence of certain classes of Abs e.g. IgA deficiency
Patients with these inherited deficiencies usually experience recurrent bacterial infection (caused by encapsulated bacteria) but have normal immunity to most viral and fungal infections
What happens to patients with antibody deficiencies?
(2)
Experience recurrent bacterial infection (caused by encapsulated bacteria)
Have normal immunity to most viral and fungal infections
Describe the different types of antibody deficiencies
Ranges from the complete absence of mature recirculating B cells, plasma cells and Abs to the selective absence of certain classes of Abs e.g. IgA deficiency
Write a note on X-Linked Agammaglobulinemia
(6)
Originally called Bruton’s agammaglobulinemia
Patients have extremely low Ab levels
Babies born with this have virtually no B cells in peripheral blood
Suffer from recurrent bacterial infections
It is caused by a defect in the gene coding for the enzyme Bruton’s tyrosine kinase (Btk) which is involved in B cell development
Developing cells in the basal membrane are arrested at the pre-BCR stage
What is X-Linked Agammaglobulinemia originally called
Bruton’s agammaglobulinemia
What are the characteristics of XLA
(3)
Extremely low Ab levels
Babies have virtually no B cells in their peripheral blood
Suffer from recurrent bacterial infections
What causes XLA?
(3)
A defect in the gene coding for the enzyme Bruton’s tyrosine kinase (Btk)
This enzyme is involved in B cell development
Developing cells in the BM are arrested at he pre-BCR stage
Write a note on phagocytic deficiencies
(3)
PIDs which result in depressed numbers of phagocytic cells or faulty cell motility, adherence, phagocytosis and intracellular killing of microorganisms
Phagocytosis mediated by macrophages and neutrophils is the principle way the immune system gets rid of infecting bacteria and other microbes
Any defect that compromises phagocyte activity had profound effects on the immune system’s capacity to clear infection
What are the characteristics of phagocytic deficiencies
(5)
Depressed numbers of phagocytic cells
Faulty cell motility
Faulty adherence
Faulty phagocytosis
Faulty intracellular killing of microorganisms
Write a note on leucocyte adhesion deficiency
(4)
LADI is caused by a mutation in the CD18 gene
CD18 is the B chain of B2 integrins that include CR3. CR4 and LFA-1, all vital for the adhesion cascade
As CR3 and CR4 also function in the complement system phagocytes are unable to engulf microbes opsonised by C3b and C4b
Patients display omphalitis, gingivitis and recurrent infections
What causes LADI
A mutation in the CD18 gene
What is CD18
(3)
CD18 is the B chain of B2 integrins
including, CR3, CR4 and LFA-1
All of these are vital for the adhesion cascade
What does loss of CR3 and CR4 do?
(2)
CR3 and CR4 play a role in the complement system
Phagocytes are unable to engulf microbes opsonised by C3b and C4b
List some symptoms of LAD1
(3)
Patients display omphalitis
Gingivitis
Recurrent infections
What does a C3 deficiency do
Susceptibility to a wide range of pyogenic infections
What does a C5-C9 and properdin deficiency do?
Susceptibility to Neisseria
What does a C1, 2 and 4 deficiency do?
Immune complex disease
What does MBL deficiency do
Increased susceptibility to bacterial and fungal infections
What does DAF or CD59 deficiency do
Autoimmunity
Paroxysmal nocturnal haemoglobinuria - erythrocytes are destroyed
What does C1 inhibitor deficiency do?
Hereditary angioedema (HAE)
Bouts of swelling of the face, larynx and abdomen
The classical pathway is overactive - low C2 and C4 and raised C2a (vasoactive component)
What is the role of the clinical immunology laboratory in the diagnosis of primary immunodeficiency
(6)
Detection of autoantibodies -> ELISA, immunofluorescence (direct and indirect)
Measurement of antibody levels - nephelometry
Measurement of specific antibody responses
Monitoring of serum proteins via serum protein electrophoresis
Measurement of complement levels/function - nephelometry, CH50, CH100 and AP50 assays
Leukocyte number/functions - flow cytometry
Why would we measure specific antibody responses
Response to vaccination
IgE to allergens
Why would we monitor serum proteins via serum protein electrophoresis?
Detection/characterisation of monoclonal gammopathy (SPE/IFE)
Detection of XLA via SPE
List the methods of measurement of complement levels
Nephelometry
CH50 assays
CH100 assays
AP50 assays
List the methods of measurement of leukocyte number/functions
Flow cytometry
What are the principles of nephelometry
(3)
Add anti-sera for protein of interest (e.g. antibodies, C3, C4 and C1 inhibitor)
Where immune complexes form they will scatter light which can be detected
Standards can be used to calculate the concentration
Nephelometry is used to detect what proteins
Antibodies
C3
C4
C1 inhibitor
Name two brands of nephelometers
Roche COBAS 6000
Binding Site OPTILITE
What is the principle of serum protein electrophoresis?
(3)
Electrophoresis is a method of separating proteins based on their physical properties
Serum is placed on a specific medium, and a charge is applied
The net charge (positive or negative) and the size and shape of the protein are used to separate and differentiate the various serum proteins
Give an example of a machine for SPE
SEBIA Hydrasys SPE system
List the different tests of the complement system
(2)
Haemolysis assays
Measurement of levels of complement components
List the different types of haemolysis assays
(2)
CH50 and CH100 -> assays of the classical pathway
Ah50 - assay of the alternative pathway
How are levels of complement components measured?
Measured via nephelometry
What levels of complement components are measured via nephelometry
C3
C4
C1 inhibitor
What is the principle of flow cytometry?
Flow cytometry is a technique for counting, examining and sorting microscopic particles suspended in a stream of fluid
Physical characteristics, size and granularity of particles are measured while fluorescently labelled antibodies can be used to examine protein expression
A laser beam is directed at a hydro-dynamically focused stream of fluid containing the cells in single cell suspension
A number of detectors measure properties such as forward scatter(size), side scatter (granularity) and fluorescence (specific protein expression) at different wavelengths
What is measured via flow cytometry
(3)
Forward scatter(size)
Side scatter (granularity)
Fluorescence (specific protein expression)
Give an example of a flow cytometer
FASCANTO II
Flow cytometry is used in the diagnosis of what?
(4)
SCID
XLA
CGD
LADI
What does SCID stand for?
Severe combined immunodeficiency
