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YEAR 5: Immunopathology JK > Immune Deficiencies 2 > Flashcards

Immune Deficiencies 2 Flashcards

1
Q

What is a Neutrophil?

A

Largest innate cell population in bone marrow?

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2
Q

Neutrophil regulation axis?

A

IL17- g-CSF axis

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3
Q

Role of Neutrophils?

A

first line of innate immunity - recruited from blood, eliminate pathogens and promote healing

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4
Q

How to neutrophils like to the adaptive immune response?

A
  • promote T cell independant Ab Production
  • enhance/suppress T cell activation
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5
Q

Structure of neutrophil and constituent parts?

A
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6
Q

IEI affecting Neutrophils?

A

Quantitative Defects (not enough)
Functional defects
1. Brining to endothelial cells - Leukocyte adhesion deficiency syndromes

2 . Generation of ROS - Chronic Granulomatous Disease

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7
Q

Thresholds for quantitative neutrophil defects

A
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8
Q

Chronic benign Neutropenia

A

Mild (usually) or moderate neutropenia
Common in number of different ancestry groups (Africa, Middle East)
Asymptomatic ( should not lead to further investigation)

  • DARc Receptor changes
  • used by plasmodium vivax
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9
Q

Severe Congenital Neuropenia

  • What
  • presentation
  • tx
A

-Several conditions involving defects in neutrophil maturation
-Different mutation in Neutrophil Elastase enzyme are commonly implicated
- Present within first 3 months of life
- Susceptible to oral, cutaneous Staphylococcal (aureus, epidermidis), G-enteric bacteria (Pseudomonas aeruginosa) and fungal (candida and aspergillus)

Genetic defects which may also involve other organ systems and can pre-dispose to haematological malignancy (MDS and AML)

G-CSF support and stem cell transplantation for high risk individuals

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10
Q

Leukocyte Adhesion Deficiency

A

Deficiency of CD18 (β2 integrin subunit)

CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

Lack of expression of adhesion molecules results in failure to exit from the bloodstream
delayed separation of umbilical cord
very high neutrophil counts in blood (20-100 x106/L)
absence of pus formation - no neutrophils In tissue

Haematopoietic stem transplantation

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11
Q

Chronic Granulomatous Disease

A

Deficiency of one of components of NADPH oxidase
Inability to generate oxygen free radicals results in impaired killing, NETosis.

Skin, lymph node, liver, bone, chest bacterial , fungal, TB and NTM infections

Excessive inflammation
Increased NF-κβ and IL-1β activation
Macrophage infiltration and granuloma
Gastro-intestinal and genitourinary inflammatory disease

Management
Cotrimoxazole and itraconazole prophylaxis
Adjunctive IFN-Y, Stem cell and gene therapy

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12
Q

How to investigate IEI neutrophil syndromes?

A
  • Check numbers
  • check functions via assays -> e.g. check oxidative burst via ability to create ROS from H2O2

DHR-123 assay -> oxidised to rhodamine which is fluorescent

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13
Q

Complement Pathway -> Activation and triggers?

A
  1. Classical (C1,2,4) via Antigen-Antibody complexes
  2. MBL via bacterial carbohydrates
  3. Bacterial cell wall activates the alternate pathway

Then C3 converts causes release of C3a,b, d and Final common pathway makes MAC

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14
Q

Complement Functions and specific subtypes ?

A

Induction of acute inflammatory responses (C3a, C5a)

Opsonisation of pathogens (C3b)

Removal of immune complexes (C1q-CR1)

Control of Neisseria infection (C5-9)

Regulation of B and T cell immune responses (C3d)

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15
Q

Complement Protein Deficiencies - Classical deficiency

A

Classical complement C1-C4-2
SLE ( C1q: 90% will develop SLE)
Susceptibility to encapsulated bacterial infections
Haemophilus influenzae type b
Streptococcus pneumoniaeC

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16
Q

Complement Protein Deficiencies - Alternative Pathway

A

Neisseria meningitis (Properdin)

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17
Q

Complement Protein Deficiencies - C3

A

Pyogenic bacterial infection
C3 glomerulopathy

18
Q

Complement Regulator Proteins

A

Complement regulatory protein (C1 inhibitor, Factors B,D, P, H I, CD46, CD55, CD59)

19
Q

Complement Protein Deficiencies - terminal complement pathway deficiency

A

Neisseria meningitis infection
Disseminated gonococcal infection

20
Q

Complement Protein Deficiencies - MBL deficieincy

A

Not clinically sig (5-30% of pop)

21
Q

Complement regulatory protein deficiency - C1 inhibitor

A

Recurrent episodes of angioedema (skin, abdomen, larynx)
Bradykinin mediated angioedema
Low C4 normal C3 absent C1 inhibitor function
Emergency therapy with C1 inhibitor (NOT Adrenaline)
Maintenance therapy (C1 inhibitor concentrate, icatibant (bradykinin antagonist) kallikrein antagonist (ecallitanide and lanadelumab)

22
Q

Complement regulatory protein deficiency - factors H/I/ MCP(CD46)

A

regulate C3 levels
C3 glomerulopathy
Atypical Haemolytic uraemic syndrome
Low C3 normal C4 absent alternative pathway function (AP50)

23
Q

Complement regulatory protein deficiency - CD55/CD59

A

PNH
haemolosys, thrombosis and pancytopenia

24
Q

How to investigate complement function

A

C3 and C4

Functional complement tests
CH50 - classical pathway
AP50 - alternative pathway

25
Q

Management of complement deficiency?

A

Screen Family
Prophylactic Abx
Vaccination against encapsulated bacteria
Aggressive tx of infections

26
Q

Role of BM in lymphocyte development

A

Lymphoid progenitors
Site of B cell development and maturation
Negative selection B cell

27
Q

Role of thymus in lymphocyte development

A

Site of T cell lineage commitment
Self-MHC-peptide positive section
Negative selection
CD4 CD8 and CD4 T regulatory cell development

27
Q

What is SCID?

A

Severe combined immunodeficiency - defects in the generation of lymphoid tissue in the BM (more than 20 conditions)

28
Q

SCID Presentation and genetics

A

** X linked or AR **

29
Q

3 Main types of SCID ?

A
30
Q

Tx of SCID

A

Stem cell transplantation
HLA matched sibling
HLA matched unrelated donor
Haplo-identical donor

Outcomes best
Age less than 3.5 months
No infection
Matched sibling donor
Survival from all donors equivalent of no infection present

31
Q

Which type of SCID has gene therapy been tried on?

A

ADA-SCID

32
Q

What type of disease is Di George Syndrome?

A

Developmental defect of pharyngeal pouch caused by a del 22q11.2

-> affects thymus and therefore T cell maturations

33
Q

Di George Syndrome - features and ix?

A

Catch 22
Cardiac abnormalities
Abnormal facies
Thymic Aplasia
Cleft Palate
Hypocalcemia
22q11.2 del

  • Low T cells, reduced IgG and improves with age
34
Q

Di George Syndrome - changes over time and tx

A

can transplant thymus to quadriceps

35
Q

Selective IgA Deficiency

A
36
Q

CVID

A

Increased susceptibility to infection

Autoimmune disease

Granulomatous disease

Lymphoproliferative disease

37
Q

CVID recurrent infections :

A

Recurrent bacterial sino-pulmonary infection with encapsulated bacteria such as Streptococcus pneumoniae and haemophilus influenzae type B

Repeated chest and sinus may result in bronchiectasis, chronic sinusitis in 20-60% of patients

Otiitis media and Haemophilus type b conjunctivitis

Enteric infection with Campylobacter jejeuni and Giardia lamblia, small bowel bacteria overgrowth syndrome

Skin: cellulitis, abscess, HSV and VZV infection

Persistent, severe, recurrent respiratory viral (rhinovirus) and norovirus infections

Normal life expectancy with IgG replacement therapy

38
Q

Dx of CVID

A

Age more than 4 years

Reduction in serum IgG and IgA and/or IgM more than 2 SD below reference interval for healthy controls

Poor vaccine responses to either carbohydrate (pneumovax) and/or protein antigen (tetanus)

39
Q

Impairment in B cell development - Brutons X linked agammaglobulinaemia

A

Mutation in BTK gene encoding Bruton Tyrosine Kinase - Pre B cells cannot develop into mature B cells

therefore after 3 months no IG, no LN and no Tonsils

40
Q
A
41
Q

Brutons X linked agammaglobulinaemia - infections

A

Recurrent bacterial pyogenic infection involving ear, nose, throat, respiratory and gastrointestinal tract infection

Microbiology: S. pneumoniae, H influenzae S aureus, and Pseudomonas spp:

Virology: unique susceptibility to disseminated enteroviral infection if not on IgG replacement therapy

YEAR 5: Immunopathology JK (13 decks)

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