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Immunology > lecture 5: Immunodeiciencies > Flashcards

lecture 5: Immunodeiciencies Flashcards

1
Q

what is the classification of immunodeficiency?

A
  • Primary - genetic or no recognized cause

* Secondary - due to something we know about

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2
Q

what is the prevalence of immunodeficiencies?

A
  • IgA deficiency - 1:300
  • Chromosome 22q deletion -1:3,000
  • Specific antibody deficiency - ?
  • Other primary immunodeficiency - 1;10,000
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3
Q

examples of a pattern of infections that are Vital clue to the type of immunodeficiency

A
  • Recurrent bacterial infections
  • Viral infections & PCP
  • Boils & Abscesses (Staph. aureus)
  • Recurrent meningococcal disease
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4
Q

what are the types of defects in humoral immunity?

A
  • Physiological
  • Primary
  • Secondary
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5
Q

what are the primary humoral immunodeficiencies?

A
  • -X-linked agammaglobulinaemia (XLA)
  • -X-linked lymphoproliferative syndrome (XLP)
  • -Common variable immunodeficiency
  • -IgA deficiency
  • -IgG subclass deficiency
  • -Defective antibody production
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6
Q

what are the secondary humoral immunodeficiencies?

A
  • -Thymoma
  • -Lymphoma
  • -B cell malignancy (CLL)
  • -Myeloma Drug therapy
  • -Post splenectomy (Immunoglobulin Loss)
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7
Q

what is the Common Variable Immunodeficiency (CVID)?

A

A primary immunodeficiency caused by B cells that are unable to differentiate into immunoglobulin-producing plasma cells, consequently leading to decreased serum immunoglobulins. Unlike most other primary immunodeficiencies, CVID is typically diagnosed after puberty, and patients usually have enlarged tonsils, lymph nodes, and/or splenomegaly.

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8
Q

what are the characteristics of CVID?

A
  • Low IgG (>2 S.D. below mean for age)
  • Low IgA or IgM
  • Onset > 2 years of age
  • Poor response to vaccines
  • Known causes of hypogammaglobulinaemia excluded
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9
Q

what are the clinical features of CVID?

A
  • Onset 2- 80s
  • Often insidious
  • Diagnosis often delayed
  • Bronchiectasis often established by the time of diagnosis
  • Associated with granulomatous inflammation
  • Autoimmunity
  • Malignancy (esp. lymphoproliferative disease)
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10
Q

how humoral immunity is assessed?

A

• Clinical history
• Measurement of Immunoglobulins IgG subclasses
Complement activity
• Serum protein electrophoresis
• Functional assessment of antibody production
– Naturally occurring antibody
– Vaccine-induced antibodies
– Test vaccination
• B cell numbers (tonsils/ blood/ bone marrow)
• B cell proliferation

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11
Q

how minor humoral defects are managed?

A
  • Antibiotics

* Vaccination

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12
Q

how significant Hypogammaglobulinaemia is managed?

A
  • IV immunoglobulin replacement
  • Sub-cutaneous immunoglobulin replacement
  • Aggressive management of infections
  • Physiotherapy/ bronchodilators/ antibiotics
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13
Q

what are the primary vs secondary causes of secondary of neutrophil dysfunction?

A

1) Primary
- -Genetic
- -Chronic granulomatous disease
- -Leukocyte adhesion defect
- -Hyper-IgE syndrome
2) Secondary
- -Drugs eg steroids
- -Diabetes mellitus

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14
Q

why diabetes causes neutrophyl dysfunction?

A

Diabetes associated with impaired mobility

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15
Q

how neutrophil function is assessed?

A
  • Clinical History
  • Blood Sugar/ IgE/ Neutrophil morphology
  • Respiratory burst
  • Chemotaxis
  • Phagocytosis
  • Adhesion/ adhesion molecule expression
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16
Q

what is the management of primary humoral defects?

A

Only cure = HSC transplantation

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17
Q

how CGD is managed?

A
  • Antibiotics – cotrimoxazole
  • Antifungals – itraconazole
  • Steroids for inflammatory complications
  • Gene therapy is in clinical trials
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18
Q

deficiency of proteins (C1,2,4) involved in the classical complement pathway is associated with?

A

immune complex disease

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19
Q

deficiency of proteins (C3, factor P and D) involved in the alternative complement pathway is associated with?

A

infection with pyogenic bacteria and Neisseria

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20
Q

deficiency of membrane attack components of complement is associated with?

A

infection with pyogenic bacteria and Neisseria

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21
Q

how complement function is assessed?

A
  • CH100 (C1,2,4,C3,5,6,7,8,9)
  • AP100 (Factor B, Properdin, C3,5,6,7,8,9)
  • Assess components likely to be abnormal
  • Measure individual components
  • Remember can have protein, but it may be mutated
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22
Q

what is the treatment for complement deficiency?

A
  • No cure
  • Vaccination
  • Prophylactic antibiotics
  • Patient education
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23
Q

what are the secondary causes of T cell/combined immunodeficiency?

A
  • HIV
  • Chemotherapy
  • Radiotherapy
  • Transplant recipients
  • Treatment for severe autoimmune disease
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24
Q

what are the primary causes of T cell/combined immunodeficiency?

A

• Severe combined immunodeficiency (SCID)
ADA deficiency
X-linked SCID & many more
• CD40 ligand deficiency (Hyper-IgM syndrome)

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25
Q

20 YEAR OLD MAN
• Recurrent cold sores for last 3 years
• Several bacterial infections
• Oral thrush (Candida)
• Now shingles affecting multiple dermatomes
What part of the immune system is likely to be involved?

A

T cells

26
Q

how T cell function is clinically assessed?

A
  • Clinical History – infections/ vaccine problems
  • HIV
  • Lymphocyte counts
  • T cell numbers & subtypes
  • Expression of TCRs, cytokine receptors etc
  • Delayed hypersensitivity skin tests
  • Vaccination with protein antigens
  • Proliferation assays
27
Q

how SCID is treated?

A 
•	Haemopoietic Stem cell transplant 
Bone Marrow
Make stem cells move into blood
•	Donors
HLA identical sibling
Parent
Matched unrelated donors
28
Q

what is the immediate management of suspected SICD?

A
  • Medical Emergency
  • Ensure adequate therapy for infections, including unusual pathogens & mixed infection
  • Irradiate all blood products
  • No live vaccinations
  • Immediate immunological investigations as an emergency
  • Consider immunoglobulin therapy
  • Early referral for Haemopoietic Stem Cell Transplant
29
Q

prophylaxis of what diseases should be accomplished in primary immunodeficiency disorders?

A
  • T cell defects – Pneumocystis jirovecii
  • CGD - co-trimoxazole & itraconazole
  • Post -Tx - CMV prophylaxis
  • Vaccination in complement deficiency
  • Antibiotics & vaccination - splenectomy
30
Q

what are the specific therapies for primary immunodeficiency disorders?

A
  • Immunoglobulin

* Bone marrow transplantation

31
Q

can we give live vaccines in patients with SCID?

A

no

32
Q

what is the Bruton aggamaglobulinemia?

A

An X-linked recessive primary immunodeficiency syndrome caused by a mutation in the B-cell tyrosine kinase (BTK) gene, which results in arrested B cell development and agammaglobulinema. Patients present with recurrent bacterial infections typically after 6 months of age. Lymphoid hypoplasia may be present on physical examination.

33
Q

what are the features of Bruton agammaglobulinemia?

A

Clinical features

  • -Onset is > 4 months after birth because of the continual decrease of maternal IgG in fetal serum.
  • -Hypoplasia of tonsils and other lymphoid tissue
  • -Recurrent, severe pyogenic infections (e.g., pneumonia, otitis media), especially with encapsulated organisms (S. pneumoniae, N. meningitidis, and H. influenzae)
  • -Hepatitis virus and enterovirus (e.g., Coxsackie virus) infection
34
Q

how Bruton agammaglobulinemia is diagnosed?

A

1) Flow cytometry
- -Absent or low levels of B cells (marked by CD19, CD20, and CD21)
- -Normal or high T cells
2) Absent lymphoid tissue (e.g., tonsils)

35
Q

what is the treatment of Bruton agammaglobulinemia

A

IV immunoglobulins

Prophylactic antibiotics

36
Q

Do live vaccines (e.g., MMR) are contraindicated in patients with Bruton agammaglobulinemia?

A

yes

37
Q

what is the x-linked lymphoproliferative syndrome?

A

X-linked lymphoproliferative disease (XLP) is a disorder of the immune system and blood-forming cells that is found almost exclusively in males. More than half of individuals with this disorder experience an exaggerated immune response to the Epstein-Barr virus (EBV)
People with XLP may respond to EBV infection by producing abnormally large numbers of T cells, B cells, and other lymphocytes called macrophages. This proliferation of immune cells often causes a life-threatening reaction called hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis causes fever, destroys blood-producing cells in the bone marrow, and damages the liver. The spleen, heart, kidneys, and other organs and tissues may also be affected. In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection.

38
Q

what is the common variable immunodeficiency?

A

A primary immunodeficiency caused by B cells that are unable to differentiate into immunoglobulin-producing plasma cells, consequently leading to decreased serum immunoglobulins. Unlike most other primary immunodeficiencies, CVID is typically diagnosed after puberty, and patients usually have enlarged tonsils, lymph nodes, and/or splenomegaly.

39
Q

what are the clinical features of CVID?

A

Recurrent pyogenic respiratory infections, e.g., sinopulmonary infections (in rare cases, enteroviral meningitis)
Associated with a high risk of lymphoma, gastric cancer, bronchiectasis, and autoimmune disorders (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, vitiligo)

40
Q

how CVID is diagnosed?

A
  • -Quantitative immunoglobulin levels: low levels of IgG, IgA, and IgM
  • -Decreased number of plasma cells
  • -Flow cytometry shows subsets of normal B and T cells
  • -Poor response to immunizations
41
Q

how CVID is treated?

A
  • -Treatment of infections
  • -Prophylactic antibiotics
  • -IV immunoglobulins
42
Q

what is selective IgA deficiency?

A

he most common primary immunodeficiency syndrome. Patients have an isolated deficiency of IgA, with normal serum levels of IgG and IgM. Clinical manifestations are highly variable and range from asymptomatic to recurrent sinopulmonary (mostly caused by encapsulated bacteria, e.g., S. pneumoniae, H. influenzae) and GI infections (e.g., due to Giardia lamblia), as secretory IgA antibodies are a crucial part of the mucosal defense. It is associated with gluten-sensitive enteropathy, inflammatory bowel disease, atopy and anaphylactic reaction to products containing IgA

43
Q

how selective IgA deficiency is diagnosed?

A
  • -Decreased serum IgA levels (< 7 mg/dL)
  • -Normal IgG and IgM levels
  • -Increased susceptibility to Giardia infection
44
Q

do we need to give IV IgA in patients with selective OgA deficiency?

A

no
Intravenous infusion of IgA is not recommended because of the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).

45
Q

what is the leukocyte adhesion deficiency type 1?

A

A congenital immunodeficiency disorder caused by a defect in leukocytic chemotaxis. An autosomal-recessive mutation of the beta-2 integrin gene leads to defective expression of CD18, which prevents leukocyte migration into tissues. Classic features develop shortly after birth and include recurrent bacterial infections, impaired wound healing, delayed separation/infection of the umbilical cord, and leukocytosis (mainly due to neutrophilia).

46
Q

what is the cause of leukocyte adhesion deficiency type 2?

A

Leukocyte adhesion deficiency type 2 results from errors in rolling due to deficiency of Sialyl-LewisX.

47
Q

what is the chronic granulomatous disease (CGD)?

A

A congenital immunodeficiency syndrome caused by an X-linked or autosomal recessive defect in the phagocytic NADPH oxidase enzyme, which results in an inability of neutrophils and macrophages to produce superoxide radicals. Affected children typically present with recurrent, severe infections of the lungs, skin, bone, and lymph nodes by catalase-positive organisms (e.g., S. aureus, Serratia, Klebsiella, Aspergillus, Burkholderia).

48
Q

how CGD is diagnosed?

A

1) Neutrophil assay
- -Dihydrorhodamine test (DHR): flow cytometry test showing abnormal NADPH oxidase activity (inability to metabolize dihydrorhodamine to fluorescent product, rhodamine → decreased green fluorescence)
- -Nitroblue tetrazolium dye reduction test: negative (Incubated leukocytes fail to turn blue when exposed to nitroblue tetrazolium. This test is rarely used in contemporary practice.)
2) Hypergammaglobulinemia
3) Genotyping is confirmatory

49
Q

what is the treatment of CGD

A
  • -Treatment of infections
  • -Life-long prophylactic antibiotics, e.g., TMP-SMX (for catalase-positive infections)
  • -Glucocorticoids for severe inflammation
  • -IFN-γ therapy
  • -Bone marrow transplant
  • -Possibly gene therapy
50
Q

what are the clinical features of CGD?

A
  • -Recurrent, severe infections (chronic skin, lymph node, bone, respiratory, GI, and urinary tract infections) with catalase-positive organisms (S. aureus, Nocardia spp., Escherichia coli, Candida, Klebsiella, Pseudomonas, Aspergillus, Serratia)
  • -Anemia
  • -Lymphadenopathy
  • -Granulomas of the skin and GI/GU tract
51
Q

what are the catalase-positive organisms?

A

A group of organisms that produce catalase, an enzyme that degrades hydrogen peroxide into water and oxygen before neutrophils can convert it via myeloperoxidase into microbicidal products. Cause recurrent infections in patients with chronic granulomatous disease. Species include Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staphylococcus, Serratia, B. cepacia, and H. pylori.

52
Q

what is the hyper-IgE syndrome (Job syndrome)?

A

A condition caused by a mutation in STAT3 that results in Th17 cell deficiency and, thus, impaired neutrophil recruitment to sites of infection. Characterized by increased serum IgE concentrations. Manifestations include coarse facial features, recurrent abscesses, retained primary teeth, and eczema.

53
Q

what are the clinical features of Job syndrome?

A

Coarse Facies

  • -Abscesses, recurrent bacterial (staphylococcal) infections
  • -Retained primary Teeth
  • -Hyper-IgE (Eosinophilia)
  • -Dermatologic (severe eczema)
  • -Other features: Decreased bone density increases the risk of bone fractures following minor trauma.
54
Q

what are the characteristic lab studies in Job syndrome?

A

↑ IgE
(Variable) eosinophilia
↓ INF

55
Q

what is the total complement activity?

A

The total complement activity test measures the capacity of serum to lyse sheep erythrocytes coated with anti-sheep antibodies (IgG). The term “CH50” refers to the dilution at which serum lyses 50% of the sheep erythrocytes. A decrease in total complement activity occurs in complement deficiencies (e.g., cirrhosis and hepatitis), while an increase is seen in proinflammatory conditions (e.g., cancer and ulcerative colitis). Measures total hemolytic complement activity (of the classical complement pathway). Hemolysis of the serum sample will be absent if the patient has a complement deficiency.

56
Q

what is the Hyper-IgM syndrome?

A

A group of immunodeficiency syndromes characterized by a class-switching defect that results in decreased levels of IgG, IgA, and IgE with normal or elevated levels of IgM. The most frequent form is an x-linked recessive CD40 ligand deficiency. Patients are at increased risk for recurrent pyogenic infections and opportunistic infection (e.g., pneumocystis, CMV).

57
Q

what are the clinical features of hyper IgM syndrome?

A
  • -Recurrent sinopulmonary infections (commonly Pneumocystis jirovecii and Histoplasma)
  • -Cryptosporidium enteritis (which may lead to biliary disease, cirrhosis, and cholangiocarcinoma)
  • -CMV hepatitis
  • -Failure to thrive
58
Q

what is the severe combined immunodeficiency (SCID)?

A

A rare and severe form of primary immunodeficiency characterized by deficiencies in both B and T cells. Etiologies include defects of the IL-2R gamma chain (most common) and deficiencies of adenosine deaminase. Patients typically develop failure to thrive and severe (often fatal), recurrent infections in the first year of life.

59
Q

what are the causes of SCID?

A

1) X-linked recessive: mutations in the gene encoding the common gamma chain → defective IL-2R gamma chain receptor linked to JAK3 (most common SCID mutation)
2) Autosomal recessive
- -Adenosine deaminase (ADA) deficiency → accumulation of toxic metabolites (deoxyadenosine and dATP) and disrupted purine metabolism → accumulation of dATP inhibits function of ribonucleotide reductase → impaired generation of deoxynucleotides
- -Janus-associated kinase 3 (JAK3) deficiency

60
Q

what are the clinical features of SCID?

A 
Normal at birth
Severe, recurrent infections: bacterial diarrhea, chronic candidiasis (thrush), viral and protozoal infections
Failure to thrive
Chronic diarrhea
Lymph nodes and tonsils may be absent
61
Q

how SCID is diagnosed

A
  • -Quantitative PCR: ↓ T-cell receptor excision circles (TRECs)
  • -Flow cytometry: absent T cells
  • -CXR: absent thymic shadow
  • -Lymph node biopsy: absent germinal centers
62
Q

how SCID is diagnosed?

A
  • -IV immunoglobulins
  • -PCP prophylaxis
  • -Bone marrow transplant or stem cell transplantation
  • -Avoidance of live vaccines
  • -Confinement to sterile environments (hence “bubble boy disease”)

Immunology (9 decks)

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