Inborne Errors of Immunity Flashcards
What are the top 3 most common causes of inborn errors of immunity?
- Antibody deficiency (37.2%)
- Well-defined syndromes with immunodeficiency (17.2)
- Conngenital defects of phagocyte number (15.95%)
- Complement deficiencies (15.95%)
Which cellular component of the immune system is the most common cause of the IEI?
B-cells (most common cause are antibody deficiencies)
What is the difference between primary immune deficiencies and familial infectious disease?
Primary immune deficiencies: immune deficiencies lead to susepibility to many differentn pathogens, with often rare and oppertunistic infectious agents (+ repeaed infectious)
Familial infectious diseases
* inherited suseptibiliy to single or few infectious diseases, e.g. mendelian susceptibility to mycobacterial disease (often only few infectitous episodes)
What is Mendelian susceptibility to mycobacterial infection? How does it cause immunodeficiency?
Familial infectious disease with low virulence against mycobateria (TB and atypical, + Salmoneally)
Abnormalitiy in IL12 and IFN y (gamma) and receptors on macrophages –> usually needed in signaling pathway to recruit cells + secrete cytokines
Therefore
1. inhibit cytokine production
2. inappropritate recruitemen of other immune cells
3. no granulomas –> suseptibiliy to infection
What is the epidemiology of IgA deficiency?
What is a common clinical presentaiton?
Relatively common: 1/600 caucasions
Usually mild presentation
* 70% asymptomatic
* recurrentt resporatory and GI infections in 30%
* Allergic disorders
* Autoimmune diseases
What are characteristic presentations for patients with Inbrn errors of Immunity?
SPUR
- Severe (sepsis, need for intravenous antibiotics or fungal drugs)
- Persistent (multiple courses of ABX needed)
- Unusual infections (e.g. opportunistic infections e.g. CMV, PJP, Live vaccine)
- Recurrent (e.g. > 2 episodes of pneumonia within a year, > 8 episodes of Otitis Media in a child)
What investigations would you order in a patient with suspected immunodeficiency?
FISH
- FBC incl. neutrophil, lymphocyte, pt
- Immunoglobulins (IgG, A, M, E)
- Serum Complement levels
- HIV test
This will pick up 85% of immunodeficiencies
How would phagocyte dficiencies present?
Recurrent, deep bacterial infections
Recurrent fungal infections
How can phagocyte deficiencies be diagnosed?
NBT or DHR flow cytometries
1. Both are dyes that change colour/ become flourescent following interaction with hydrogen peroxide (present on most phagocytes)
How are phagocyte deficiencies managed?
- Aggressive Management of infection
- Prophylaxis: Antibiotics and Antifungals
Definiitive treatment
1. Haematopoietic stem clel transplant ( to “replace” defective population of cells
What is a typical presentation of Complement deficiencies?
Increased susceptibiliy tto encapsulated bacterial infections (esp. if classical pathways affected)
+ Neisseria Meningiditis in some deficiencies (C9)
How are complement deficiencies diagnosed?
Why is it not sufficient to just measure C3+C4 levels?
Measurment of CH50 and AP50
this measures complement PATHWAY, not just levels of individual complements
Often C3 and C4 levels are normal (as most common deficiencies ar eC1q, C9 and Factor B)
- CH50: measures activity of classical Complement 1-9 (patients blood are covered with antibodies and lysis of erythrocytes measured. if high complement –> high lysis)
- AP50: Measures Activiy of alernative complemen pathway, same principle as CH50
How sould someone with a complement deficiency be treated?
Vaccination
Prophylactic antibiotics
High level of suspicion+ early treatment advised, treat family members
What is Severe Combined Immunodeficiency?
Group of rare genetic disorders that cause defects in the generation of lymphoid precursors in bone marrow (aka no functional B or T cells in bone)
Various mutations with different patterns of inheritance
Pathophysiology: many different thigns play together + different mechanisms can cause it
What is the clinical presentation and prognosis of Severe combined Immunodeficiency (SCID)?
Usualls presents early as recurrent infections <3 months, failure to thrive etc.
? abscent tonsils/ lymph nodes
(X-linked recessive or autosomal recessive)
Usually fatail within 1 year of life if untreated. Definitive treatment: stem-cell transplant (outcomes best if <3.5 months of life)
How is SCID diagnosed?
Severe combined immunodeficiency
- Low lymphocyte count (counts are normally much higher in children than in adults
- CD3 T cell count < 300cells/uL
- T cell proliferation < 10% of control
- Low serum immunoglobulins
Flow cytometry
T- B+ SCID
T-B-SCID
What is DiGeorge syndrome?
What is it’s epidemiology?
22q11.2 deletion syndrome
Genetic syndrome characterized by defective development of the third and fourth pharyngeal pouches leading to hypoplastic thymus and parathyroids –> immunodeficiency
Epidemiology
* most common deletion syndrome
* 1 in 1.000 (90% are de Novo deletions), others autosomal dominant
What is a clinical presentation of DiGeorge syndrome?
- Cardiac abnormalities (ASD, VSD, tetralogy of fallot)
- Thymus agensis –>T-cell deficiency leading to recurrent/ abnormal infections
- Facial abnormalities (e.g. cleft palate, ohers)
- Parathyroid gland dysfunction –> hypocalcaemia
How is a selective IgA deficiency diagnosed?
Serum IgA less than 0.07g/L
With normal serum immunoglobulins
vaccine responses and B and T cell counts
What is common variable immune deficiency?
Primary immunodeficiency with low serum levels of all immunoglobulins despite phenotypically normal B cells (failure of B-cells to differentiate)
+ presents with auto-immune + sometimes granulomatous disease?
What is the epidemiology of CVID (Common varibale immune deficiency?
Commonest cause of primary antibody deficiency - aetiology largely unknown
1 in 20,000 to 1 in 50,000 individuals
Bimodal age of onset
* 30% <10
* Adult median age 35
Primary immunodeficiency with low serum levels of all immunoglobulins despite phenotypically normal B cells
What is the clinical presentation of CVID?
Common varibale immuno sufficiency
1. Recurrent infections (sinusitis, conjunctivitis, skinetc.) with encapsulated bacteria such as Streptococcus pneumoniae and haemophilus influenzae type B)
2. 20-30% also auto-immune + granulomatous diseases
3. Increased risk of B-cell NHL and gastric cancer
What is the management of CVID?
- Managemen of infections + complications : ABX + physio etc.
- Prevention: Prophylactic antibiotics + IgG replacement therapy
How is CVID diagnoised?
CVID: normal B cells but antibody deficiency
- age >4
- Reduced AB (IgG + IgA/ IgM) > 2SD under reference range
- poor vaccine response
- exclusion of other causes (drugs, B-cell lymphoma)
What is X-linked agammaglobulinaemia (XLA)
Also known as Bruton agammaglobulinemia
X-linked recessive disease that causes a complete deficiency of mature B lymphocytes
( due to defect defect of Bruton tyrosine kinase (BTK) needed for maturation of B-cells )
What is the clinical presentaiton of Bruton agammaglobulinemia? (XLA)
X-linked agammaglobulinaemia
Usuall in boys
* presents 3-6 months (when maternal IgG in fetal falls)
* lymphoid tissue hypoplasia
* recurrent pyogenic infection with encapsulated bactteria
* hepatitis + enterovirus infection
How is XLA diagnosed? (Bruton agammaglobulinaemia)?
X-linked agammaglobulinaemia
- Flow cytometry:
- Absent or low levels of B cells (marked by CD19, CD20, and CD21)
- Normal or high T cells
- Low immunoglobulins of all classes
- Absent lymphoid tissue, i.e., no germinal centers and primary follicles
Generally: what are common clinical features of T-cell deficiencies?
What are common clinical features of Antibody deficiency (or CD4 T cell deficiency)?
