3.2 Causes of Immunodeficiency

Question 1

Reticular dysgenesis results from a mutation in the mitochondrial energy metabolism enzyme ______________:
• AK2 is required for the development of mature immune cells, so there is a failure of production of _________________
• Fatal in very early life (unless corrected with BM transplantation)

Answer 1

adenylate kinase 2 (AK2);

neutrophils, lymphocytes, monocytes and platelets

Question 2

Chronic granulomatous disease may be X-linked or autosomal recessive:

Clinical features

1. Deep seated infection (liver, perirectal, lung abscess, lymphadenitis, osteomyelitis) caused by Aspergillus, Staphylococcus, Candida or Serratia marcescens
2. Diffuse granulomata in respiratory, GI, or urogenital tracts
3. Failure to thrive (insufficient weight gain/inappropriate weight loss), hepatosplenomegaly, lymphadenopathy

Pathogenesis
- Absent respiratory burst (due to deficiency of one of the components of ____________ ) results in inability to generate oxygen free radicals and thus impaired killing of intracellular microorganisms:
• Causes excessive inflammation and persistent phagocyte accumulation (failure to degrade antigens)
• Causes formation of _________________________

Answer 2

NADPH oxidase;

granulomas, lymphadenopathy, hepatosplenomegaly

Question 3

Severe combined immunodeficiency (SCID) is the absence/dysfunction of T cells affecting both cellular and adaptive immunity:
• Innate immune system is intact, but the lack of T cells (and thus affecting B cell maturation and activation) leads to significant immunodeficiency
• 20 pathways identified, with the most common being ____________ (45%) and the most severe being _____________

Answer 3

X-linked SCID ;

reticular dysgenesis

Question 4

X-linked SCID is caused by a mutation of the ________________ on chromosome Xp13.1, resulting in an inability to respond to cytokines:
• Early arrest of ____________________ and production of _______________-
• DDx: HIV infection, DiGeorge syndrome, congenital rubella syndrome, MHC class II deficiency, purine nucleoside phosphorylase (PNP) deficiency

Investigations: __________ T cell numbers, ____________ B cell numbers (non-functional), _____________ lymphoid tissues and thymus

Clinical presentation: Unwell by 3 months of age, infections of all types, failure to thrive, persistent diarrhoea, family history of early infant death, unusual skin diseases (colonisation of infant’s empty BM by maternal lymphocytes, GVHD)

Pathogenesis: IgG in the _________________ protects the SCID neonate in the first 3 months of life:
• IgG production in breastmilk declines after 3 months, and normal neonates begin producing IgG (none in SCID)
• IgA is the main antibody in breastmilk, but all 5 are present

Prognosis

• Early diagnosis: 80% survival (if no pre-transplant infection and with good SC donor match)
• Late diagnosis: 40% survival (if pre-transplant infection and poor SC donor match)

Treatment: Stem cell transplantation (from HLA-identical sibling) is ideal:
• Possible for SCT from matched unrelated donors Gene therapy (currently in 2nd phase trials) involving BM harvesting from the SCID infant:
• ______________ are selected, then stimulated by cytokines
• Corrected receptor gene is then transferred into the stem cells via gene transfer then cells are infused back
• Allows new generation of T cells to develop in the thymus

Answer 4

gamma chain of the IL-2 receptor;

T cell and NK cell development;

immature B cells;

Reduced/absent;

normal/increased;

poorly developed;

colostrum and subsequent breastmilk;

CD34+ stem cells

Question 5

DiGeorge syndrome is a developmental defect of the ______________________ (which give rise to the thyroid, parathyroids, thymus):
• Mutation is sporadic in 75% of patients, involving _________________ leading to failure of thymic development (hypoplasia/aplasia) & immunodeficiency

Clinical features: High forehead, low set abnormally folding ears, ___________ (with small mouth and jaw), ________________ (from hypoparathyroidism), _______________ atresia, T cell lymphopenia, velopharyngeal dysfunction
• Complex congenital heart diseases in 75% of cases (tetralogy of Fallot, interruption of aortic arch, persistent truncus arteriosus)
• Developmental delays and psychiatric disorders (OCD, schizophrenia) Investigations

Normal B cell numbers, reduced T cell numbers (not complete loss): Homeostatic proliferation occurs with age (thus immune function improves) → prognosis depends on concomitant problems Treatment

1. BM/thymic transplantation
2. Cardiac surgery (to correct abnormalities)
3. Management of hypoparathyroidism and other issues

Answer 5

3rd and 4th pharyngeal pouches;

deletion at chromosome 22q11;

hypocalcaemia;

cleft palate;

oesophageal;

Question 6

Bare lymphocyte syndrome type II occurs due to a deficiency in \_\_\_\_\_\_\_\_\_\_\_\_\_\_: 
• Intermediate precursor T cells differentiate into \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ if they have affinity for HLA class II 

Pathogenesis: Due to defect in one of the regulatory proteins involved in class II gene expression (e.g. regulatory factor X, class II transactivator, absent expression of MHC class II molecules) → cannot stimulate _____________________

Clinical features: Unwell by 3 months of age (before that, IgG from breastmilk is protective), infections of all types, family history of early infant death, failure to thrive:
• May be associated with ____________

Investigations: _____________ of CD4+ cells (usually with normal CD8+ cell numbers and normal B cell numbers; but fail to make __________)

*Bare lymphocyte syndrome type I also exists and is due to failure of HLA class I expression.

Answer 6

MHC class II molecules;

CD4+ T helper cells;

B cell Ig class switching (requires CD4+ T cell help);

sclerosing cholangitis ;

Profound deficiency;

IgG or IgA

Question 7

What can cause meningoencephalitis?

Answer 7

Enteroviruses

Question 8

What can cause conjunctivitis?

Answer 8

Haemophilus influenzae

Question 9

What can cause sinusitis and pneumonia?

Answer 9

Streptococcus pneumoniae, Haemophilus influenzae

Question 10

What can cause skin infection?

Answer 10

Staphylococcus aureus

Question 11

What can cause GI infection?

Answer 11

Giardia lamblia, Campylobacter spp.

Question 12

What can cause cystitis?

Answer 12

Ureaplasma urealyticum

Question 13

CD40 ligand deficiency is an intrinsic T cell defect in the CD40 ligand gene, resulting in the failure of CD40L expression on activated T cells:
• T cells cannot facilitate B cell activation (no costimulatory signals → may result in anergy), causing _______________________

Clinical features: Male patients present in the first few years of life (X-linked) with recurrent bacterial infections and failure to thrive:
• _______________ infections are important

Investigations: Normal circulating B cell numbers, normal T cell numbers and in vitro T cell responses, ___________ serum IgM (no class switching), undetectable ____________, no GC development in LNs and spleen, failure of isotype switching

Answer 13

failure of Ig class switching and secondary B cell maturation defect;

Pneumocystis jirovecii;

elevated;

IgA, IgE, IgG

Question 14

IgA deficiency often presents with a less severe clinical picture, with complete IgA deficiency affecting 1 in 600 Caucasian individuals:
• Genetic and environmental factors are important in the development of disease
• Associated with ______________ (in 30% of patients) → IgA is involved in innate defence at the epithelium

Answer 14

recurrent respiratory and GI tract infections

Question 15

X-linked agammaglobulinaemia (Bruton’s syndrome) occurs due to a mutation in a ___________________:

• Disruption of B cell signalling causes B cell maturation arrest at ____________
• DDx: autosomal recessive agammaglobulinaemia (due to μ heavy chain, λ5 CD79a, and BLNK deficiencies)

Clinical features: Male patients tend to develop recurrent chest, ear, and joint bacterial infections (before the age of 2), systemic sepsis and neutropenia (resolves as the patient gets better)
• Most common causative organisms are __________________
• Up to 20% of patients present after the age of 5

Answer 15

B cell tyrosine kinase signalling protein (Btk);

pro-B cell stage;

H. influenzae and S. pneumoniae

Question 16

CVID is a heterogeneous group of disorders which display varying degrees of antibody deficiency (hypogammaglobulinaemia):
• Disease mechanism is unknown

Clinical features: Onset of symptoms occurs in the 2nd – 4th decades of life
• Recurrent bacterial ______________ infections
• Antibody deficiency (hypogammaglobulinaemia)
• Autoimmune disease (20%): ITP, AIHA, PA, thyroid disease
• Granulomatous disease involving the lungs, liver, spleen, skin (10%)
• Increased risk of ___________________

Answer 16

sino-pulmonary and GI ;

non-Hodgkin’s lymphoma and gastric cancer

Question 17

The functions of the complement system and proteins include:

1. ______________ of pathogens (promotes pathogenesis)
2. Increases ______________ and cell trafficking to the site of inflammation
3. Causes ______________ (MAC punches holes in bacterial cell membranes)
4. Promotes __________________

The three different complement pathways converge in C3 cleavage and the final common pathway, which forms the membrane attack complex (MAC):
• Risk of infections: particularly with
___________ bacteria (if alternative/final pathways are involved)
• Family history of susceptibility to infections (meningitis)
• Systemic lupus erythematosus (SLE): less clearance of _______________ → increased load of self-antigens and autoimmunity (if classical pathway is involved)

[Deficiency]

Classical pathway

1. _____ deficiency (100% SLE-like illness)
2. _____ deficiency (75% SLE-like illness)
3. ______ deficiency (10 – 30% SLE-like illness)
   - Increased susceptibility to __________

Mannose-binding lectin (MBL): Mutations in the ____________ causing reduced production or abnormal function of the MBL subunit
- Recurrent pyogenic infections in childhood, increased susceptibility to Saccharomyces cerevisiae infections (and pneumococcal and Neisseria infections)

Alternative pathway: X-linked disorder due to ________ deficiency (positive regulator of complement activation)
- Increased risk of ____________

C3 deficiency: Rare condition resulting from various mutations (> 17 types) in the C3 gene
- Pyogenic infection, vasculitis

Terminal pathway (MAC): Rare condition involving mutations leading to deficiency of C9 (involved in MAC formation)
- Increased risk of \_\_\_\_\_\_\_\_\_\_\_\_\_

Answer 17

Opsonisation;

vascular permeability;

bacterial cell lysis;

mast cell/basophil degranulation;

encapsulated ;

apoptotic/necrotic cells;

C1q; C4; C2;

encapsulated bacterial infections;

MBL2 gene;

properdin;

Neisseria infections;

Neisseria infections

Question 18

CH50 test for??

Answer 18

Tests for deficiencies in the classical pathway

Question 19

AP50 tests for?

Answer 19

ests for deficiencies in the alternative pathway

Question 20

ELISA/other techniques tests for?

Answer 20

Measures levels of individual complement proteins

Question 21

Patients with complement deficiencies should be managed via the following:
• ___________ meningococcal vaccine
• Prophylactic _______
• Pneumovax and Haemophilus influenzae B (HIB) vaccine
• Immunosuppressive therapy for SLE-like complications

Answer 21

Tetravalent;

penicillin

Question 22

DIABETES MELLITUS
Diabetes increases the susceptibility of a patient to many infections (especially of the skin and urinary tract) due to hyperglycaemia, vascular disease and sensory neuropathy:

Skin infections
1. Diabetic foot disease (foot infections) are the most common infections seen
• Predisposed by ______________ (cannot tell when foot is injured) and _______________ (decreased perfusion to the foot)
• Specialised Diabetic Foot Clinics minimise the impact and improve quality of life for these patients
2. Cellulitis and staphylococcal sepsis (more common in diabetic patients)
• Minor infections: often ____________
• Severe necrotising infections: polymicrobial (surgical debridement)

Urinary tract infections (UTIs)
1. Bacteriuria, cystitis, pyelonephritis
• Higher risk of complicated infections (treated with a longer course of antibiotics) )
2. Genitourinary infections
• Balanitis (inflammation of the glans penis) is caused by __________ is an important hint that patient has diabetes → check blood glucose

Answer 22

sensory neuropathy;

microvascular disease;

S. aureus;

Candida

Question 23

OLD AGE
The influenza vaccine has an efficacy of 70 – 90% in young adults (especially when the vaccine strain resembles the epidemic strain), but drops to 30 – 40% in elderly:

Causes
- Immune senescence
• Increased frequency of ______________ in the elderly
• Increased expression of senescence markers
• Largely reduced production of _____________ which drives the naïve T-cell repertoire
- Nutrition*
• Insufficient energy due to poor nutrition (sometimes due to poor dentition → less able to chew and ingest food)
• Reduced availability of_______________ (reduced gut absorption)
*Studies which gave subjects nutritional supplements showed fewer days of URTI symptoms, greater increase in serum antibody titre to influenza vaccine, and better lymphocyte proliferation to vaccine components.

Answer 23

terminally differentiated effector memory T cells;

recent thymic emigrants;

trace elements and minerals

Question 24

PREGNANCY
Pregnancy is not a state of generalised immunodeficiency, but pregnant women are more susceptible to some specific pathogens (especially certain viruses):
• May have a significant impact on maternal and foetal health (e.g. VZV causes more severe infections involving ______________ in pregnant women)

Period
- Early pregnancy: Pro-inflammatory (response to ___________ → essentially creates an open wound in the uterus)
• Causes cytokine release and inflammation (may be involved in morning sickness in the 1st trimester)
- Middle phase: _____________-
- Delivery: Pro-inflammatory (requires inflammatory response in the __________ to promote contraction)

Answer 24

pneumonitis and encephalitis;

implantation and placentation;

Anti-inflammatory ;

myometrium

Question 25

The treatment and prognosis of secondary immunodeficiency depends on the cause:

• Diabetes: More intensive management peri- and post-operatively (diabetic patients are more likely to succumb to infection postop due to slower healing)
• Pregnancy: Aggressive treatment of infections to ameliorate effects (for certain viral infections like VZV)
• HIV infection: Controlled using ________________ to suppress viral replication and thus viral load

Answer 25

highly active antiretroviral therapy (HAART)

Question 26

NEUTROPENIA The normal neutrophil range is ______________, with exceptions to this range including:

1. Ethnic: Afro-Caribbean males (1 – 5.8 x 109/L
2. Age: 2 month old baby (0.7 – 4.7 x 109/L)
3. Pregnancy: 2nd trimester (3.8 – 12.3 x 109/L)

Abnormality

• Decreased production: Post-viral infection, drugs (including chemotherapy), vitamin deficiency (___________), aplastic anaemia
• Replacement of _______________: Leukaemia, lymphoma, myelofibrosis
• Increased peripheral destruction: Hypersplenism, autoimmunity (e.g. SLE, autoimmune neutropenia)

MANAGEMENT
The management of febrile neutropenic sepsis includes taking a good history and examination, followed by empirical antibiotics:
• History taking: ask if patient is known to be neutropenic (e.g. recent chemotherapy)
• Empirical antibiotics: if patient presents with a single oral temperature of > 38.3°C or a temperature of > 38.0°C for more than 1 hour, isolate and prompt treatment (within 1 hour) with empirical antibiotics (e.g. pip/tazo, amikacin)
• _________: stimulates bone marrow to produce neutrophils

Answer 26

2 – 7.5 x 109/L;

B12/folate;

haematopoietic tissue;

G-CSF