Immune Deficiencies Flashcards
Reticular Dysgenesis
Autosomal Recessive SCID
AK2 mutation = adenylate kianse 2 in mitochondria responsible for energy production
Causes failure of stem cells to differentiate along MYELOID AND LYMPHOID linage
Failure of production of: Neutrophils Lymphocytes Monocyte/macrophages Platelets Fatal in very early life unless corrected with bone marrow transplantation
Kostmann Syndrome
Autosomal recessive severe congenital neutropenia
Solely affects neutrophil maturation
HAX1 mutation
Cyclic Neutropenia
Autosomal dominant episodic neutropenia
Every 4-6 weeks
Neutrophil elastase (ELA-2) mutation
Leukocyte Adhesion Deficiency
Deficiency of CD18 / B2 integrin
CD11a/CD18 on neutrophil bind to endothelium and facilitate extravasation
Causes:
Very high neutrophils in the blood
Absence of pus formation
Chronic Granulomatous Disease
Failure to generate respiratory burst
NADPH oxidase deficiency
Persistent neutrophil/macrophage accumulation
Formation of Granuloma
Lymphadenopathy and hepatosplenomegaly
Can give IFN-y to activate additional pathways in place of oxidative killing
Nitroblue tetrazolium (NBT) test AND Dihydrorhodamine (DHR) flow cytometry test
Combined = can neutrophils kill through production of oxidative free radicals
Nitroblue tetrazolium NBT
NBT is a dye that changes colour from yellow –> blue, following interaction with hydrogen peroxide
(Nellow to Blue)
Dihydrorhodamine DHR
DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide
Treatment of phagocyte deficiencies
Aggressive management of infection Infection prophylaxis Septrin – antibiotic Itraconazole – anti-fungal Oral/intravenous antibiotics as needed Surgical draining of abscesses
Definitive therapy Bone marrow transplantation ‘Replaces’ defective population Specific treatment for CGD Interferon gamma therapy
Immunodeficiency involving phagocytes
Reticular dysgenesis
Kostmann syndrome (congenital neutropenia)
Leukocyte adhesion deficiency
Chronic granulomatous disease
IL12 /IFN gamma cytokine or receptor deficiency
Activation of the Complement Cascade
Classical = antibody-mediated
Lectin = MBL to microbial cell surface carbohydrates
Alternative = Spontaneous breakdown of C3
Classical Pathway
Antibody-antigen complex (C1–>C4–>C2)
Antibody changes shape –> allows C1 to bind
C1 –> C1a
C1a –> C4 to produce C4b + C4a
C4b + C2 –> C3
Lectin Pathway
Mannose-binding lectin (MBL) C4 and C2
(independent of acquired response)
Activated by the direct binding of MBL to microbial cell surface carbohydrates
Directly stimulates the classical pathway, involving C4 and C2
Alternative Pathway
Spontaneous, C3 BIP pathway
Directly triggered by binding of C3 to bacterial cell wall components
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria
Not dependent on acquired immune response
Involves factors B, I and P
Features of Complement Deficiency
Susceptibility to infection Particularly with encapsulated bacteria – if alternative / terminal pathway involved Neisseria meningitides (Meningococcus) Streptococcus pneumoniae (Pneumococcus) Group B streptococcus Haemophilus influenza
FHx of meningitis
SLE
If early classical pathway missing
Classical complement pathway is involved in clearance of apoptotic/necrotic cells
Also these immune complexes will do more damage once they have developed as they won’t be solubilised and cleared – role of complement
More likely to get skin disease with SLE
ALSO
SLE causes secondary deficiency
C4 levels falls
Then C3 levels fall
Secondary Causes of Complement Deficiency
SLE
C4 levels falls
Then C3 levels fall
Due to increase consumption in solubilising immune complexes
Auto-immune condition activating C3 convertase
Nephritic Factor
auto-antibodies directed against components of the complement pathway
Associated with Glomerulonephritis (classically membranoproliferative)
Associated with partial lipodystrophy
Abdomainal fat distribution
Loss in upper half of body
Investigation of the Complement Pathway
Measure complement levels
C3 and C4 routine
C1 inhibitor: decreased in hereditary angioedema
Functional complement tests
CH50 classical pathway
AP50 alternative pathway
Immunodeficiency involving complement
Classical pathway deficiencies MBL deficiency Alternative pathway deficiencies C3 deficiency Terminal pathway deficiencies
Phenotype of SCID
SCID --> Graft vs Host Disease Unwell by 3 months Infections of all types Failure to thrive Unusual skin disease Maternal lymphocyte colonise infants bone marrow --> Graft vs Host FHx of early infant death
Protected for first 3 months:
Maternal IgG crosses placenta
Maternal antibodies protect neonate for first 3 months of life
IgG in colostrum - Neonate gut can still absorb antibodies
X-Linked SCID
X-linked SCID = 45% of all SCID
Chromosome X: IL-2R gamma chain mutation (Xq13.1)
Receptor chain is shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 RECEPTORS
Inability to respond to cytokines –> arrested T cell and NK development –> don’t produce
Able to produce immature B cells
Phenotype
Low/Absent T cells
Normal/High B cells (immature)
Poorly differentiated lymphoid tissue and thymus
DiGeorge
Chromosome 22q11.2 deletion syndrome
Forehead –> heart defects
Defect in development of the pharyngeal pouch
Thymus under developed
Majority of cases mild defect with generation later on
Phenotype High forehead Low set, abnormally folded ears cleft palate, small mouth and jaw Hypocalcaemia Oesophageal atresia T cell lymphopenia Complex congenital heart disease
Normal numbers B cells Reduced numbers T cells Homeostatic proliferation with age Immune function usually only mildly impaired and improves with age
Bare Lymphocyte Syndrome Type II
Type II = MHC II deficiency
MHC II deficiency –> lack of selection of CD4 cells –> deficiency in CD4 cells
Mutation in MHC II regulatory proteins (NOT MHC II gene themselves)
Regulatory Factor X
Class II transactivator
Absent MHC II expression –> Lack of CD4 cells
Normal CD8 cells
Normal number of B cells
But deficiency of IgG and IgA as need CD4 to class switch
Phenotype Unwell by 3 months Failure to thrive Infections of all type FHx of early infant death
Associated with Sclerosing Cholangitis
IL-12 - IFN-y Deficiency
Causes IL-12 def IL-12 R def INF-y def INF-yR def
Infected macrophage –> produces IL-12 –> acts on T cells, produce IFN-y –> acts back on macrophages –> Increase in TNF and NADPH oxidase activity
Susceptibility to: Tuberculosis Atypical mycobacteria BCG infection after immunisation Salmonella
Inability to form granulomas
Immunodeficiency Involving T cells
Severe combined immunodeficiency (SCID)
22q11.2 deletion syndromes
Bare lymphocyte syndrome
IL12 receptor deficiency
IFN gamma deficiency
Management of T cell Deficiencies
Infection prophylaxis
Aggressive treatment of infection
Immunoglobulin replacement
If there is associated deficient antibody production
Bone marrow transplantation
To replace abnormal populations in SCID
To replace abnormal cells - class II deficient APCs in BLS
Gene therapy
Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo.
Experimental
Thymic transplantation
To promote T cell differentiation in Di George syndrome
Cultured donor thymic tissue transplanted to quadriceps muscle
- Experimental
Bruton’s X-Linked Hypogammaglobulinaemia
Abnormal B cell tyrosine kinase gene = diagnostic
Pre-B-Cells cannot differentiate into mature B cells
Deficiency of mature B cells
No circulating antibodies after 3 months
Recurrent infections during childhood
Bacterial
Enterovirus
Hyper IgM Syndrome
X-linked genetic defect in the CD40L Chromosome Xq26 (TNF receptor family)
Defect in CD4 cells that manifests as B cell defect
CD40L is expressed by ACTIVATED CD4 cells –> activates B cells and induces class switching
Deficiency of CD40L
Intrinsic T cell defects
Hyper IgM B cells: can differentiate into plasma cells BUT no class-switching (no germinal centre reaction)
Normal number of T cells Normal number of B cells No IgA, No IgG Elevated IgM in serum No germinal centre development in the lymph nodes/spleen Failure of isotype switching
Presentation Boys present in first few years Failure to thrive Autoimmune disease Malignancy Pneumocystis jiroveci (PCP) infection
Intrinsic T cell defect –>Defective T cell regulation and apoptosis
- -> T cell-impaired immunity (PCP)
- -> Autoimmunity
- -> Malignancy
Selective IgA Deficiciency
IgA deficiency
1 in 600
2/3 asymptomatic and don’t notice
1/3 recurrent respiratory tract infections
Genetic component, but cause as yet unknown
Common Variable Immune Deficiency
Low IgG, IgA and IgE
Recurrent bacterial infections
Cause unknown
Failure in differentiation of plasma cells
Defined by
Marked reduction in IgG, with low IgA or IgM
Poor/absent response to immunisation
Absence of other defined immunodeficiency
Reccurent infections
Particular sinusitis and chest infection
And non-infectious inflammatory diseases
Clinical features – adults and children
Recurrent bacterial infections
Often with severe end-organ damage
Sinusitis, pneumonia, gastroenteritis
Pulmonary disease
Obstructive airways disease
Interstitial lung disease
Granulomatous interstitial lung disease (also LN, spleen)
Gastrointestinal disease
Inflammatory bowel like disease
Sprue like illness
Bacterial overgrowth
Autoimmune disease Autoimmune haemolytic anaemia or thrombocytopenia Rheumatoid arthritis Pernicious anaemia Thyroiditis Vitiligo
Malignancy
Non-Hodgkin lymphoma
Management of B cell deficiencies
Aggressive treatment of infection
Immunoglobulin replacement
Derived from pooled plasma from thousands of donors
Contains IgG antibodies to a wide variety of common organisms
Aim of maintaining trough IgG levels within the normal range
Treatment is life-long
Bone marrow transplantation
To ‘replace’ abnormal populations – SCID, X-linked hyperIgM
Immunisation
For selective IgA deficiency
Not otherwise effective because of defect in IgG antibody production
B Cell Deficiencies
Severe combined immunodeficiency (SCID) X-linked Bruton’s hypogammaglobulinaemia X-linked hyperIgM syndrome Common variable immunodeficiency IgA deficiency
T cell Deficiencies
Bare Lymphocyte Syndrome
DiGeorge’s Syndrome
X-linked tyrosine kinase deficiency
Bruton’s Agammagloulinaemia
X-linked Xq26 CD40L defect
Hyper-IgM Syndrome
HAX-1 autosomal recessive defect
Kostmann Syndrome
B2/CD18 defect
Leukocyte adhesion deficiency
NADPH oxidase deficiency
Chronic Granulomatous Disease
ELA-1 gene defect
Cyclic neutropenia
