Immunodeficient Disorders

Question 1

States of immune deficiency

Answer 1

1. Primary immunodeficiency

2. Secondary (acquire) immunodeficiency

Question 2

Primary immunodeficiency

Answer 2

Results form genetic or developmental defect in the immune system
Affect either adaptive or innate immune functions
Categorized by type of cell involvement or developmental stage defect occurs
Affect cells of lymphoid or myeloid lineages and involve specific genes
Depending on affected component, varying levels of susceptibility to infection

Question 3

Reticular dysgenesis

Answer 3

Stem cells fail to differentiate, causing total lack of leukocytes

Question 4

Lymphoid immunodeficiencies

Answer 4

Involve B cells, T cells or both (sometimes NK cells)

Effect is mainly adaptive immune response

Question 5

Lymphoid immunodeficiencies: B cell defects

Answer 5

Range from complete absence of B cells, plasma cells and Ig to selective loss of certain Ig
Result in frequent bacterial infections due to the absence of humoral immunity, especially encapsulated bacteria
Immunity to most viral and fungal infections is normal

Question 6

Lymphoid immunodeficiencies: T cell defects

Answer 6

Result in frequent viral and fungal infections due to absence of cell-mediated immunity
Humoral immunity to T-dependent antigens is also affected
Some decrease in antibody levels

Question 7

Severe combined immunodeficiency (SCID)

Answer 7

Family of disorders that effects either T cells, or both T and B cells
Common cause is defects in cell interaction and signaling molecules
Deficiency in gamma chain of IL2R and JAK-3 kinase impedes critical signaling
CD3 zeta chain deficiency only affects T cells
Defect in RAG-1 and RAG-2 causes T and B cells not to differentiate
Severe and recurrent infections that usually lead to death in early life
Live or attentuated vaccines can kill
Life can be prolonged by confinement to a sterile environment
Treatment by bone marrow transplant
Gene therapy is possible treatment but can cause cancer due to use to retroviral vectors

Question 8

DiGeorge Syndrome (congenital thymic aplasia)

Answer 8

Developmental defect in which children are born without thymus or parathyroid (sometimes thyroid is not completely absent)
Few functional T cells so cell-mediated immunity is absent
B cells are present but cannot make specific antibody in response to infection or vaccination because of lack of T helper cells
Transplantation of fetal thymus can help

Question 9

BC Immunodeficiency: X-linked agammaglobulinemia

Answer 9

1 in 1000-1000000 males
Pre-B cells in bone marrow do not differentiate
Defect in Brunton’s tyrosine kinase required to couple pre-BCR to nuclear events causing light chain rearrangement and BC maturation
Little or no circulating antibody
Can be treated with injections of purified pooled IgG
Sinopulmonary infections persist due to lack of secretory IgA

Question 10

BC Immunodeficiency: X-linked hyper-IgM syndrome

Answer 10

Defect in gene coding for CD40 ligand
CD40 on B cells must interact with CD40 ligand on T cells for B cell activation to occur
Response to T-independent antigens is normal, leading to heightened IgM production
IgG, IgA and IgE are absent as there is no class switching

Question 11

BC Immunodeficiency: Selective immunoglobulin deficiencies

Answer 11

One antibody class or subclass is missing
Most common is IgA, due to failure of IgA-committed B cells to differentiate into plasma cells (increased allergies with IgE production, treatment is with broadspectrum antibiotics)

Question 12

Myeliod cell immunodeficiencies

Answer 12

Affect innate immunte function, especially phagocytosis

1. Congenital neutropenia
2. Chronic granulomatous disease
3. Leukocyte adhesion deficiency (LAD)

Question 13

Myeliod cell immunodeficiencies: congenital neutropenia

Answer 13

Decreased production of granulocyte-colony stimulating factor (G-CSF)
Myeloid stem cels fail to differentiate into neutrophils
Frequent bacterial infections are common as neutrophil-mediated phagocytosis is absent

Question 14

Myeliod cell immunodeficiencies: chronic granulomatous disease

Answer 14

Defect in oxidative pathway that phatocytes use to generate hydrogen peroxide
Phagocytes unable to kill many types of phagocytosed bacteria
Excessive inflammatory response and susceptibility to bacterial and fungal infections
Antigen processing and presentation to macrophages is impaired

Question 15

Myeliod cell immunodeficiencies: leukocyte adhesion deficiency (LAD)

Answer 15

Failure to express the beta subunit of adhesion molecules LFA-1, MAC-1(CR3), and gf150,90(CR4)
Required for cell interactions, nearly absent from membrane
Impaired extravasation of neutrophils, monocytes and lymphocytes
Impaired ability of CTL and NK to adhere to target cells
Failure of T helped cells and B cells to form conjugates
Frequent bacterial infections and impaired wound healing

Question 16

Defects in the complement system

Answer 16

1. In early components of classical
2. C3 deficiencies
3. C5-C9 deficiencies
4. In Factor D or properdin

Question 17

Defects in the complement system: deficiencies in early components of classical complement

Answer 17

CIq, Clr, C1s, C2, C4
Prevents generation of C3 convertase
Absence of C3b (opsonin) causes frequent bacterial infections and immune complex disease due to failure to cleare immune complexes by phagocytosis

Question 18

Defects in the complement system: C3 deficiencies

Answer 18

Most severe
Cause frequent bacterial infections
No opsonization by C3b and failure to form MAC
Results in autoimmune complex disease
Impairs immune complex clearance by phagocytosis

Question 19

Defects in the complement system: C5-C9 deficiencies

Answer 19

Cause few health problems
Increased incidence of infections by Neisseria species that are normally susceptible to lysis by MAC
Immune complex disease is rate (enough C3b produced for clearance)

Question 20

Defects in the complement system: Factor D or properdin

Answer 20

Required for proper function of alternative pathway

Result in susceptibility to infection by Neisseria species

Question 21

Acquired immunodeficiencies

Answer 21

AIDS
Can be caused by immunosuppressive drugs
Chemotherapeutic agents

Question 22

Acquired Immunodeficiency Syndrome (AIDS)

Answer 22

Progressive loss of immune responsiveness due to infection and death of CD4+ T helper cells by HIV-1 retrovirus
Macrophages and dendritic cells are infected
Death due to pulmonary infections, cancer, CNS complications
Spreads by sexual contact, infected blood, mother to infant
Infect via CD4 chemokine receptors that act as coreceptors

Question 23

Chemotherapeutic agents

Answer 23

Ie. cisplatin
Toxic to proliferating bone marrow stem cells, T cells and B cells
Loss of immune function

Question 24

Immunosuppressive drugs

Answer 24

ie. Cyclosporin A and rapamycin
To prevent organ graft rejection
Interfere with normal T cell responses
T cells are present but not responsive
Can result in overwhelming infections and can increase the incidence of certain cancers, especially lymphomas