Immunodeficiency Flashcards
Which immunodeficiency in common? primary or secondary?
Secondary immunodeficiency (due to disease or medication)
(It is encountered by physician on a daily basis in routine practice)
What are the pattern of infection in immunodeficiency?
- Neutrophil defects
- Complement deficiency
- B cell/antibody deficiency
- T cell deficiency
Primary Immunodeficiency: Classification >> Major categories
- Neutrophil disorders/deficiencies
- Complement deficiencies
- B cell/antibody disorders/deficiencies
- T cell disorders/deficiencies
- Combined B & T cell disorders/deficiencies
Primary immunodeficiency: Neutrophil defects
Mnemonic ‘CCL’
- Chronic granulomatous disease
- Chediak-higashi syndrome
- Leukocyte adhesion deficiency
Primary immunodeficiency: complement defects
The most importants are >>
- C1q deficiency
- C1INH deficiency
- Final common pathway defects
- & many others
Primary immunodeficiency: B cell/Antibody disorders
Mnemonic ABC
- IgA** deficiency**
- Bruton’s congenital agammaglobulinaemia
- Common variable immunodeficiency (CVID)
Primary immunodeficiency: T-cell defects
DiGeorge syndrome
Secondary immunodeficiency >> Example by categories
-
Neutrophil defect:
- Diabetes mellitus
-
Complement deficiency:
- Eculizumab therapy
-
B cell/ Antibody defect:
- Chronic lymphocytic leukaemia (CLL)
- Rituximab
- Phenytoin
- Gold
-
T-cell defect:
- HIV infection
- Ciclosporin
- Anti-CD3 therapy
Primary immunodeficiency: Combined B and T cell defects
Mnemonic: SCID WAS Ataxic
- SCID (Severe combined Immunodeficiency)
- Ataxia Telangiectasia
- Wiskott-Aldrich syndrome
Neutrophil defects are associated with-?
Recurrent bacterial or fungal skin infection (Cellulitis/Abscess)
Neutrophil defects: Examples
-
Primary: CCL
- Chronic granulomatous disease
- Chediak-higashi syndrome
- Leukocyte adhesion deficiency
- Secondary: Diabetes mellitus
Complement deficiency: identification
It may be uncovered incidentally (as NOT always symptomatic)
The most important clinical association with complement deficiency-?
- Hereditary angioedema (C1-inhibitor deficiency)
- SLE (C1q deficiency)
What does happen if there is “final common pathway” defect?
Recurrent/invasive Neisseria spp. infections
Complement deficiency: Examples
-
Primary:
- C1q deficiency
- C1-INH deficiency
- ‘final common pathway’ deficiencies
- Secondary: Eculizumab treatment
Eculizumab >> mechanism
C5 inhibitor
Eculizumab >> Indication
PNH (Paroxysmal nocturanl haemoglobinuria)
(Its a complement mediated RBC cell lysis)
Eculizumab: Main side-effect
Secondary complement deficiency
B-cell/antibody deficiency >> results in??
- Sinopulmonary infections
- Bronchiectasis
B-cell/antibody deficiency: Examples
-
Primary ABC
- Selective IgA deficiency
- Bruton’s agammaglobulinemia
- Common variable immunodeficiency
-
Secondary
- Chronic lymphocytic leukaemia (CLL)
- Rituximab
- Gold
- Phenytoin
Chronic Granulomatous Disease: Inheritance
Variable pattern of penetrance
Mainly X-linked recessive
Which is more common between IgA deficiency and IgG2 deficiency?
Primary IgA deficieny is more common than IgG2 deficiency in population
IgA deficiency: main pathophysiology
Maturation defect of B cell
IgA deficiency: Features
NO sign-symptoms
can cause bronchiectasis
Time period of >>
Bruton’s congenital agammaglobulinaemia
Common variable immunodeficiency (CVID)
- Bruton’s agammaglobulinaemia: within 1st 18months
- CVID: late teenage
Bruton’s congenital agammaglobulinaemia: Inheritance
X-linked recessive
Bruton’s congenital agammaglobulinaemia: pathophysiology
- Mutation in Bruton’s kinase
- Defective maturation of B cell ( = NO/less formation of plasma cells = less Ig production)
- Immunoglobulin (Ig) deficiency
Common variable immunodeficiency (CVID): manifestations
- Impaired function of antibody response >>> recurrent sino-pulmonary infections
-
2 or more Ig are reduced among >>> IgA, IgM, IgG
- More common: IgA reduction
- More reduced: IgG (than IgM)
- No sign-symptoms
T-cell deficiency >> results in-?
The following opportunistic infections
- Pneumocystis jirovecii
- Invasive virus (e.g. CMV: Cytomegalovirus)
- Intracellular bacteria (e.g. Salmonella)
- Mycobacteria
T-cell deficiency: Examples
-
Primary
- DiGeorge syndrome
-
Secondary
- HIV infection
- Cyclosporin
- Anti-CD3 therapy
-
Combined B + T cell deficiencies (primary) Mnemonic: SCID WAS Ataxic
- Severe combined immunodeficiency (SCID)
- Wiskott-Aldrich syndrome
- Ataxia telangiectasia
DiGeorge syndrome >> type of genetic disorder
Microdeletion syndrome
DiGeorge syndrome: type of infections
Viral and fungal infections (high risk)
(As it is a T-cell defect)
DiGeorge syndrome: genetic defect
Chromosome 22 deletion (chromosome 22q11 anomaly)
DiGeorge syndrome: Features
Above downwards
- Learning disabilities
- Hypertelorism (increased distance between 2 orbits)
- Abnormal ear
- Cleft palate, short philtrum
- Micrognathia
- Maldevelopment of pharyngeal pouch
- NO parathyroid development >>> hypocalcaemia >>> tetany
-
NO development of normal thymus
- Normal B cell (rests are low)
- Reduced T cell production
- Reduced IgG response
- Reduced IgA response
- Congenital heart disease
- Defect in great vessels
- Hypocalcaemia (low calcium level)
Combined B-cell and T-cell disorder: Inheritance
- Severe combined Immunodeficiency (SCID): X-linked recessive
- Wiskott-Aldrich syndrome: X-linked recessive
- Ataxia telangiectasia: Autosomal recessive
SCID (Severe combined Immunodeficiency): Enzyme defect
Reduced ADA (Adenosine deaminase) enzyme
SCID (Severe combined Immunodeficiency): Pathophysiology
ADA (Adenosine deaminase enzyme) normally converts >>>
- Deoxyadenosine to deoxynosine (AND, also)
- Adenosine to inosine
In SCID >>> reduced ADA >>> so,
- High deoxyadenosine, low inosine etc.
>>> deoxyadenosine is toxic to lymphocytes (both B and T cells) [especially immature T cells of thymus]
Wiskott Aldrich Syndrome: gender ratio
Mainly male (as X-linked recessive)
Type of Immunoglobulin deficiency in Wiskott-Aldrich syndrome and Ataxia telangiectasia
- Wiskott-Aldrich syndrome >>> IgG, IgM deficiency
- Ataxia telangiectasia >>> IgA deficiency
Wiskott Aldrich syndrome and Ataxia telagiectasia: Common features
- Recurrent chect infections
- Haematological malignancy (lymphoma, leukaemia, non-lymphoid tumours)
- Melignancy
Wiskott Aldrich syndrome: genetic defect
mutation in “WASP” gene
Wiskott Aldrich syndrome: Features
- Thrombocytopaenia
- Low IgG, Low IgM
- Humoral immunodeficiency
- Recurrent chect infections
- Severe bacterial infection
- Eczema
- Autoimmunity
- Malignancy
- Haematological cancer (leukaemia, lymphoma etc.)
Wiskott Aldrich syndrome: Life expectancy
6 to 30years
Wiskott Aldrich syndrome: Main cause of death
Bleeding (maybe due to thrombocytopaenia)
Ataxia telangiectasia: Features
-
10% risk of developing maligancy
- Lymphoma
- Leukaemia
- Non-lymphoid tumours
- Recurrent chest infections
- Low IgA
Job syndrome >> Another name?
Hyper-IgE syndrome
Job syndrome is named after whom?
It is named after Job in the Bible
who was plaged with boils
Job syndrome: pathophysiology
Failure of intracellular signalling in JAK-STAT pathway >>> Multiple immune failures >>> both: innate & adaptive responses
Job syndrome: Clinical features
Mnemonic: FATED
- Facies: Coarse or leonine
- Abscess: Cold abscess by staphylococcus spp.
- Teeth: Retention of primary teeth
- E: High IgE
- Dermatological problems: Eczema
Manifestations are heterogenous
It is one of the very few diseases that is associated with >>> Cryptococcus pneumonia (Cryptococcus neoformans)
Job syndrome: 2 main organisms & their manifestations
- Staphylococcus spp. >>> cold abscess
- Cryptococcus neoformans >>> Cryptococcal pneumonia
Why is Job syndrome important regarding pathophysiology?
It has failue in ‘intracellular signalling’ in the JAK-STAT pathway
& JAK-STAT pathway has been earmarked as the next major immune pathway to inibit in the treatment of autoimmune diseases
JAK inhibitor >> Indication
Cryptococcal pneumonia
FDA licensed the first JAK inhibitor in 2012
