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IMED2001 > Body Defences: Immunodeficiency > Flashcards

Body Defences: Immunodeficiency Flashcards

1
Q

What kind of immunodeficiency defects can arise?

A

Quantitative Functional (affecting maturation or activation/effector functions)

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2
Q

What is the predicted consequences of immunodeficiency?

A

Increased susceptibility to newly acquired infections Reactivation of latent infections Increased incidence of some malignancies

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3
Q

What clinical features suggest primary immunodeficiency?

A

Recurrent +/- severe infections Opportunistic organisms Unusual infections Severe infections with organisms of low pathogenicity Failed response to therapy/recur soon after therapy is ceased Family members with known Primary Immunodeficiency

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4
Q

What are the types of immunodeficiency?

A

Primary (congenital) Secondary (acquired immunodeficiencies)

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5
Q

What kind of conditions can cause immunodeficiency?

A

Genetic abnormalities in one or more components of the immune system. Infections Drugs Protein losing states Haematological disorders

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6
Q

When can primary immunodeficiency first show up?

A

It can occur in infancy or during adulthood.

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7
Q

What kind of diseases affect people with T cell deficiencies?

A

Viral and intracellular microbial infections

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8
Q

What kind of diseases affect people with B cell deficiencies?

A

Pyogenic bacterial infections, enteric bacterial infections, and viral infections.

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9
Q

What histopathological abnormalities are seen in people with reduced B cells and T cells?

A

B cells: reduced or absent follicles and germinal centers in lymphoid organs + reduced serum Ig levels T cells: Reduced T cell zones in lymphoid organs. Reduced DTH reactions to common antigens, defective T cell proliferative responses.

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10
Q

What genetic defects affect lymphocyte maturation?

A

Severe Combined ImmunoDeficiency (X-SCID due to γc mutations) ADA and PNP deficiencies Defects in maturation of B-lymphocytes (X-linked aγglubulinemia) Defects in maturation of T-lymphocytes (Di George Syndrome)

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11
Q

What functional deficiencies are present in people with X-linked SCID?

A

Markedly decreased T cells and either normal or increased B cells. This results in reduced serum Ig due to loss of T help.

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12
Q

What is the mechanism of the defect in X-linked SCID?

A

Cytokine receptor common γ chain gene mutation due to lack of IL-7 signals.

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13
Q

What fucntional deficiencies are present in autosomal recessive SCID?

A

Progressive decrease in T and B cells (mostly T cells)

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14
Q

What is the mechanism of defect in autosomal recessive SCID?

A

ADA or PNP deficiency leads to accumulation of toxic metabolites in lymphocytes.

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15
Q

What causes X-linked SCID?

A

>99% are due to mutations in the common γc chain signalling subunit of receptors for several cytokines - IL-2, 4, 7, 9, 15, 21.

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16
Q

What is the result of the mutation in the γ chain in T lymphocytes?

A

Immature lymphocytes cannot proliferate in response to IL-7. Reduced maturation and maturation of lymphocyte precursors (mainly affects T cells) Profound decrease in the numbers of mature T cells and deficient CMI.

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17
Q

Why is NK cell activity reduced in response to γc chain mutations?

A

Due to the importance of IL-15 in NK proliferation and maturation.

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18
Q

Why is the humoral immune system’s activity reduced in response to γc mutations?

A

Due to absence of T cell help (B cells may mature normally but this is still an issue)

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19
Q

What percentage of SCID disorders are X-linked?

A

50%

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20
Q

Where does the mutation occur in 99% of X-linked SCID?

A

In the γ chain (the blue chain)

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21
Q

Where else can mutations occur besides the γ chain?

A

JAK3, STAT5 and IL-7Rα

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22
Q

What kind of SCID are ADA and PNP deficiencies?

A

Autosomal recessive

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23
Q

What happens during ADA and PNP deficiencies?

A

Mutations in autosomal genes that encode proteins involved in nucleic acid metabolism.

ADA deficiency leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA (proliferating cells) such as lymphocytes undergoing maturation.

Deficiency in PNP leads to a similar phenotype.

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24
Q

What do ADA and PNP stand for?

A

Purine Nucleotide Phosphate

Adenosine DeAminase

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25
Q

What mutations lead to SCID?

A

X-linked: γc chain -> IL 2, 4, 7, 9, 15, 21 deficiency

Autosomal -> ADA and PNP, JAK3 (similar effect to γc), RAG1 or RAG2 (rare cases)

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26
Q

What are the clinical features of SCID?

A

Profound susceptibility to infection from early infancy:

Chronic mucocutaneous candidiasis, opportunistic infections, severe/fatal infections with viral pathogens, attenuated live vaccines can cause disease

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27
Q

What kind of pneumonia is common in SCID patients?

A

PJP pneumonia (aka Pneumocystis pneumonia (PCP))

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28
Q

How is SCID managed?

A

Aggressive search for and treatment of infections

Protective isolation and no attenuated live or live vaccines

Replacement immunoglobulin

Prophylaxis for bacterial, viral and fungal infections

Haematological stem cell transplant - treatment of choice - source of normal T/B cells

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29
Q

What is X-linked Aγglobulinemia?

A

The most common syndrome associated with B-cell maturation block.

Failure of expansion of pre-B-cells in bone marrow due to mutations in the gene encoding a kinase called Bruton tyrosine kinase (BTK) leading to defective production or function of the enzyme. This results in decrease or absence of mature B-cells and immunoglobulins.

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30
Q

What happens to people with X-linked Aγglobulinemia?

A

Maternal IgG supplies antibodies for the first 6 months of life and then when this protection is no longer available the patients start to develop infections.

In 25% of patients there is an autoimmune response. (arthritis)

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31
Q

What are the theories as to why X-linked Aγglobulinemia causes autoimmunity in 25% of people?

A

BTK contributes to B cell receptor signalling and is required for central B cell tolerance.

Defective BTK may result in the accumulation of autoreactive B cells.

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32
Q

What is Di George syndrome?

A

The most frequent selective defects in T cell maturation due to incomplete development of thymus and parathyroid glands. This results in failure to develop mature T cells.

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33
Q

What are the clinical features of Di George syndrome?

A

The condition improves with age due to development of thymus. The small amount of thymic tissue that does develop at a young age is able to support some T cell maturation but not enough. They present with similar symptoms to people with SCID.

Facial features (can be subtle)

Hypocalcaemia (aplastic parathyroids)

Cardiac abnormalities

Aplastic/hypoplastic thymus

34
Q

What are the types of Di George syndrome?

A

Absence of thymus

Hypoplastic thymus (have some degree of immune deficiency and T-cell + B-cell deficits as well as recurrent sino-pulmonary infections.

35
Q

What are the possible defects in B cell responses?

A

Hyper-IgM syndrome

Genetic deficiencies in the production of selected immunoglobulin isotypes

Common variable immunodeficiency (CVID)

36
Q

What are the possible defective activation conditions of T lymphocytes?

A

Bare lymphocyte syndrome

Selective T-cell deficiency

37
Q

What is hyper IgM syndrome?

A

It is an X-linked condition due to defective B-cell heavy chain isotype switching.

Mutations in the X chromosome gene encoding CD40L. (The helper T cell protein that binds to CD40 on B cells, DCs, and macrophages and thus mediates T cell dependent activation of these cells)

38
Q
A
39
Q

What is the result of CD40L deficiency?

A

Defective T cell - dependent macrophage activation in CMI

Defective T cell - dependent B cell responses, such as isotype switching and affinity maturation in humoral immunity.

Deficient cell-mediated immunity against intracellular microbes.

40
Q

What kind of pathogen are people particularly susceptible to in hyper-IgM syndrome?

A

Boys with this disease are especially susceptible to infection by pneumocystis jirovecii, a fungus that survives within phagocytes in the absence of T cell help.

41
Q

What is normal CD40 - CD40L interaction important for?

A

Initiation of T cell response

Activation of B cells (isotype switching, antibody production, and cytokine secretion)

Activation of macrophages (enhanced phagocytosis, cytokine secretion, and MMP secretion)

42
Q

How problematic are genetic deficiencies in production of selected immunoglobulin isotypes? What causes these deficiencies?

A

They are quite common and don’t cause any clinical problems in most patients.

The defect causing these deficiencies is often unknown but may be caused by mutations to Ig heavy chain constant region.

43
Q

What is common variable immunodeficiency (CVID)?

A

A heterogeneous group of disorders resulting in poor antibody responses to infections (Reduced IgG, IgA and often IgM).

44
Q

What causes common variable immunodeficiency?

A

Underlying causes include defects in genes involved in B cell maturation and activation.

Some patients have mutations in genes encoding receptors for B cell growth factors or co-stimulators that play a role in T-cell <-> B-cell interactions.

45
Q

How does CVID present?

A

Variable age of onset:

25% are <20yo

most others are 20 - 40 yos

Infections - 60 - 80% have sinopulmonary infections (encapsulated bacteria)

Gi infections are common (campylobacter jejuni, giardia)

20% less common infections (meningitis, sepsis, cutaneous infections)

Non-infectious complications - Autoimmune cytopenias, growth delay, and others

46
Q

What is bare lymphocyte syndrome?

A

Mutations in transcription factors that induce expression of MHCII molecules resulting in no MHCII on CD4+ T cell surface

47
Q
A
48
Q

What is selective T cell deficiency?

A

Mutations affecting various signalling pathways or cytokines and receptors involved in differentiation of naive T cells into effector cells.

Affected patients show severe T cell deficiency or deficiency in particular arms of T CMI depending on the mutation and the extent of defect. (i.e defects in Th1 or 17 resulting in deficiency in response to their respective pathogens)

49
Q

Where can immune responses be blocked?

A

Genetic defects can arise in::

Expression of molecules required for antigen presentation to T cells

T or B lymphocyte antigen receptor signalling

Helper T cell activation of B cells and macrophages

Differentiation of antibody producing B cells

Activation Induced Deaminase

IL-12R

IFNγR

50
Q

What kind of defects can arise in neutrophils?

A

Defects in neutrophilic homing

Defects in adhesion molecules

Defects in phagocytosis

Defects in killing

51
Q

What causes chronic granulomatous disease?

A

Mutation in genes encoding subunits of enzymes that catalyze the production of microbicidal ROS in lysosomes.

52
Q

What is the result of the lack of killing in chronic granulomatous disease?

A

Neutrophils and macrophages are unable to kill microbes, they accumulate and recruit more neutrophils and macrophages to site, collection of phagocytes resembling granulomas accumulate around foci of infections.

53
Q

What is the most common cause of granulomatous disease?

A

Mutations of a subunit of the phagocyte oxidase enzyme gene on the X chromosome.

54
Q

What are the clinical manifestations of chronic granulomatous disease?

A

Recurrent infections by pathogens normally killed by oxidative burst especially catalase positive bacteria and fungi: Staph aureus, burkholderia cepacia, serratia, nocardia, aspergillus.

Granuloma formation in skin, bone, liver, and GI tract.

55
Q

What causes leukocyte adhesion deficiencies?

A

Mutations in genes encoding:

Integrins

Molecules required for expression of ligands for selectins.

Signalling molecules activated by chemokine receptors.

56
Q

What is the result of leukocyte adhesion deficiencies?

A

Blood leukocytes can’t migrate to peripheral tissues and so are not recruited normally to site of infection.

57
Q

What is the result of C3 deficiency?

A

Severe infection and can be fatal. (C3 is essential for the entire system to work)

58
Q

What is the result of C2 and C4?

A

Increased bacterail and viral infection and increased immune-complex formation (due to defective clearance of immune complex)

59
Q

What is the result of C5 - C9 deficiency?

A

Associated with susceptibility to Neisseria species infections

60
Q

What happens if complement regulatory proteins are deficient?

A

Deficiencies of complement regulatory proteins lead to excessive complement activation.

61
Q

Why is deficiency of C5 - C9 associated with neisseria infection?

A

Due to deficiency in MAC formation

62
Q

How are primary immunodeficiency diseases treated generally?

A

Infections are treated with antibiotics as needed.

Replacing the defective gene is ideal.

63
Q
A
64
Q

How are SCID diseases treated?

A

It is fatal in early life unless patient’s immune system is reconstituted. Haematopoietic stem cell transplants with careful matching of donor and recipient and it is the most widely used treatment.

65
Q

How are selective B cell defects treated?

A

Intravenous injections of pooled immunoglobulin from healthy donors to provide passive immunity.

66
Q

How is X-linked agammaglobulinemia treated?

A

IVIG replacement therapy

67
Q

How is X-linked SCID treated?

A

Successful gene therapy has been reported. A normal γc gene was introduced into their bone marrow stem cells which were transplanted back into the patients.

68
Q

How are secondary immunodeficiency disorders treated?

A

Treating the causes (eg HIV antiretrovirals)

69
Q

What receptors does HIV interact with? How does it interact with them?

A

CD4 and Chemokine receptors. HIV-1 uses gp41 and gp120 to bind to these 2 receptors.

70
Q

What does the HIV-1 virus contain?

A

2 identical strands of RNA

Associated enzymes (reverse transcriptase, integrase, and protease)

A cone-shaped core composed of p24 capsid protein with a surrounding p17 matrix

All surrounded by a phospholipid membrane envelope derived from the host cell.

71
Q

How does HIV cause disease?

A

HIV spreads from initial site of infection to lymphoid tissues throughout the body.

The virus infects CD4+ T cells, dendritic cells, and macrophages at sites of entry through epithelia.

In mucosal tissues at site of entry there may be a considerable destruction of infected T-cells, including large proportion of memory T cells with marked functional deficit.

Immune responses of the host temporarily control acute infection but not chronic infection.

Cytokines produced in response to HIV and other microbes enhance HIV production and progression to AIDS.

AIDS develops over many years as latent HIV becomes activated and destroy cells of the immune system

72
Q

What happens to viral load and T cell count as HIV progresses?

A

Blood-borne virus (plasma viremia) is detected early after infection +/- symptoms.

Virus spreads to lymphoid organs and plasma viremia falls to very low levels for many years - clinical latency.

CD4 count steadily declines during clinical latency period due to active viral replication in T cells.

73
Q

Clinical course of HIV disease:

A
74
Q

What causes immunodeficiency in AIDS?

A

Depletion of T cells

Functional abnormalities in T lymphocytes, DCs and macrophages

75
Q

What are potential complications that can arise from HIV infection?

A
76
Q

What other indications are there for immunosuppressive therapies?

A

Solid organ transplantation

Haematopoietic stem cell transplantation (bone marrow or blood)

Autoimmune or inflammatory disorders (systemic or organ specific)

77
Q

What cancers can cause secondary antibody deficiencies?

A

B cell lymphoproliferative disease (CLL/NHL)

Myeloma

Thymoma-associated immune defects

Medications or medical procedures

Immunosuppressant drug therapy

Splenectomy

Haematopoietic stem cell transplantation

78
Q

What kind of infections are common in people with no spleen?

A

Acute overwhelming infections with encapsulated bacteria (strep pneumoniae, Haemophilus influenzae B, Neisseria meningitidis).

Infection with blood-borne parasites (malaria, and babesiosis)

79
Q

How is asplenia managed?

A

Education

Antibiotic prophylaxis

Emergency antibiotic supply

Vaccination

80
Q

Why is there a high risk associated with bone marrow transplant?

A

Due to combination of:

Myeloablative therapies

Degree of immune reconstitution

Impaired barrier function

Graft vs host disease

81
Q
A
82
Q
A

IMED2001 (44 decks)

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