Immunodeficiency Diseases

Question 1

Disorders in which a part of the body’s immune system is missing or dysfunctional

Answer 1

Immunodeficiencies

Question 2

Clinical symptoms associated with immunodeficiencies

Answer 2

Ranges from very mild or subclinical to severe, recurrent infections or failure to thrive

Question 3

Two Types of Immunodeficiencies

Answer 3

Inherited and Acquired

Question 4

Example of a secondary immunodeficiency

Answer 4

Acquired Immunodeficiency Syndrome (AIDS), which is caused by the
human immunodeficiency virus (HIV)

Question 5

Affects primarily males

Answer 5

Immunodeficiency syndromes with X-linked inheritance

Question 6

Exception to that primary immunodeficiencies (PIDs) are rare disorders with a combined incidence of about 1 in 1,200 live births

Answer 6

Immunoglobulin A (IgA) deficiency

Question 7

Some PIDs have their primary effect on B cells and humoral immunity

Answer 7

whereas others mainly affect the cell-mediated branch of the adaptive immune system

Question 8

In general, defects in humoral immunity (antibody production)

Answer 8

Results in pyogenic (i.e., pus-forming) bacterial infections, particularly of the upper and lower respiratory tract. Recurrent sinusitis and otitis media (i.e., ear infections) are common.

Question 9

The clinical course of viral infections in patients with predominantly antibody deficiencies is not significantly different
from that in normal hosts, with the exception of _____

Answer 9

Hepatitis B, which may have a fulminant course in patients with agammaglobulinemias, conditions in which antibody levels in the blood are significantly decreased.

Question 10

Defects in T-cell–mediated immunity result in

Answer 10

Recurrent infections with intracellular pathogens such as viruses, fungi, and
intracellular bacteria.

Question 11

Patients with congenital T-cell deficiencies

almost always develop

Answer 11

• Mucocutaneous candidiasis, a yeast infection that involves the skin, nails, and mucous membranes.
• They are also prone to disseminated viral infections, especially with latent viruses such as herpes simplex, varicella zoster, and cytomegalovirus.

Question 12

Because T cells also play an important role

in tumor immunity,

Answer 12

Patients with these conditions are more susceptible to developing certain types of cancer

Question 13

Age-adjusted rates of malignancy in patients with immunodeficiency disease are

Answer 13

10 to 200 times greater than those observed in immunocompetent individuals

Question 14

Most of the malignancies are

Answer 14

Lymphoid and may be related to persistent stimulation of the remaining immune cells, coupled with defective immune regulation.

Question 15

Neutrophils are the first line of defense against invading organisms

Answer 15

Defects in neutrophil function are usually reflected in recurrent pyogenic bacterial
infections or impaired wound healing.

Question 16

Abnormalities in macrophage function will have effects on ______

Answer 16

Both the innate and the adaptive defenses because macrophages are involved in the
nonspecific phagocytosis of microorganisms during inflammation as well as in the processing of antigens and their presentation to T cells in humoral and cell-mediated immune responses

Question 17

Reduction in the macrophage population by splenectomy is associated with _____

Answer 17

An increased risk of overwhelming bacterial

infection accompanied by septicemia

Question 18

The complement system is activated directly by antigens or by antigen–antibody complexes to produce biologically active
molecules that enhance inflammation and promote lysis of microorganisms.

Answer 18

Deficiencies of complement components result in recurrent bacterial infections and autoimmune-type manifestations. The severity of the conditions varies with the particular complement component that is deficient.

Question 19

In many cases, it appears that deficiency of

one component of the immune system is accompanied by hyperactivity of other components

Answer 19

This may occur because persistent
infections continuously stimulate the available immune cells or because a compensatory mechanism has been activated to correct for the deficient immune function.

Question 20

In addition, the deficiency may involve a component that normally exerts regulatory control over other components of the immune system—control that is lacking in the deficiency state. For instance, T helper (Th2) cells secrete cytokines that regulate the
development of B cells into plasma cells.

Answer 20

Defect in Th2 cell function, such as a deficiency in CD40L (a molecule involved in
binding to cell receptors during T-dependent immune responses), removes or creates an imbalance in the regulation of those immune
responses.

Question 21

Whatever the mechanism, many partial immunodeficiency states are associated with allergic or autoimmune manifestations

Answer 21

Currently referred to as autoinflammatory disorders

Question 22

The Nine Categories of Primary Immunodeficiencies (PIDs)

Answer 22

• Category 1: Combined Immunodeficiencies
• Category 2: Combined Immunodeficiencies With Associated or Syndromic Features
• Category 3: Predominantly Antibody Deficiencies
• Category 4: Diseases of Immune Dysregulation
• Category 5: Congenital Defects of Phagocyte Number, Function, or Both
• Category 6: Defects in Innate Immunity
• Category 7: Autoinflammatory Disorders
• Category 8: Complement Deficiencies
• Category 9: Phenocopies of Primary Immunodeficiencies

Question 23

In the past, the immunodeficiencies have been broadly classified as defects in T cells, B cells, phagocytes, complement proteins,
and other components of the innate immune system. As scientific knowledge has been gained about the complexity of these disorders, experts have recognized that such a broad classification is overly simplistic.

Answer 23

In 2014, the International Union of Immunologic Societies (IUIS) updated their classification of PIDs by grouping them into nine different categories based on their characteristic clinical features, immunologic defects, and genetic abnormalities. The IUIS has also published diagnostic flow charts to aid in classifying patients into a disease entity based on clinical symptoms and laboratory results.

Question 24

The conditions in this category are the most common immunodeficiencies, representing about 50% of the PIDs

Answer 24

Category 3,

Predominantly Antibody Deficiencies

Question 25

This category encompasses conditions in which the main characteristic is low levels of serum immunoglobulins

Answer 25

Category 3: Predominantly Antibody Deficiencies

Question 26

Immunoglobulins migrate in the “gamma region” of the serum protein electrophoretic profile...

Answer 26

Therefore, deficiencies of immunoglobulins have been termed agammaglobulinemias

Question 27

The mechanisms of the agammaglobulinemias include ____

Answer 27

Genetic defects in B-cell maturation or | mutations leading to defective interactions between B and T cells.

Question 28

Deficiency: All antibodies; especially IgG ``` Level of Defect: Slow development of helper function in some patients ``` Presentation: 2–6 months; resolves by 2 years

Answer 28

Transient hypogammaglobulinemia of infancy

Question 29

Deficiency: IgA; some also with reduced IgG2 Level of Defect: IgA-B cell differentiation Presentation: Often asymptomatic

Answer 29

Selective IgA deficiency

Question 30

Deficiency: All antibody isotypes reduced Level of Defect: Pre–B-cell differentiation Presentation: Infancy

Answer 30

Btk deficiency

Question 31

Deficiency: Reduced antibody; many different combinations Level of Defect: B cell; excess T suppression Presentation: Usually 20–30 years of age

Answer 31

Common variable immunodeficiency

Question 32

Deficiency: Reduced IgG1, IgG2, IgG3, or IgG4 Level of Defect: Defect of Isotype Differentiation Presentation: Variable with the class and degree of deficiency

Answer 32

Isolated IgG subclass deficiency

Question 33

Deficiency: Reduced IgG, IgA, IgE, with elevated IgM Level of Defect: B-cell switching Presentation: Variable

Answer 33

CD154 deficiency

Question 34

The blood level of IgG at birth is about the same as the adult level, reflecting transfer of maternal IgG across the placenta.

Answer 34

The IgG level declines over the first 6 months of life as maternal antibody is catabolized.

Question 35

Levels of IgA and IgM are very low at birth.

Answer 35

The concentrations of all immunoglobulins | gradually rise when the infant begins to produce antibodies at a few months of age in response to environmental stimuli.

Question 36

IgM reaches normal adult levels first, around 1 year of age, followed by IgG at about 5 to 6 years of age.

Question 37

In some normal children, IgA levels do not reach normal adult values until adolescence.

Answer 37

Therefore, it is important to compare a child’s immunoglobulin levels to age-matched reference ranges.

Question 38

All infants experience low levels of immunoglobulins at approximately 5 to 6 months of age; however, in some babies the low levels persist for a longer time.

Answer 38

Because these children do not begin synthesizing immunoglobulins promptly, they can experience severe pyogenic sinopulmonary and skin infections as protective maternal IgG is cleared.

Question 39

Cell-mediated immunity is normal and there may be normal levels of IgA and IgM.

Answer 39

Transient Hypogammaglobulinemia | of Infancy With Normal Numbers of B Cells

Question 40

IgG appears to be the most affected, dropping to at least 2 standard deviations (SDs) below the age-adjusted mean with or without a depression of IgM and IgA

Answer 40

Transient Hypogammaglobulinemia | of Infancy With Normal Numbers of B Cells

Question 41

Immunoglobulin levels in infants with this condition usually normalize spontaneously, often by 9 to 15 months of age

Answer 41

Transient Hypogammaglobulinemia | of Infancy With Normal Numbers of B Cells (mechanism not yet known)

Question 42

These patients have normal numbers of circulating CD19+ B cells. This condition does not appear to be X-linked, although it is more common in males. The cause may be related to a delayed maturation of one or more components of the immune system, possibly Th cells

Answer 42

Transient Hypogammaglobulinemia | of Infancy With Normal Numbers of B Cells

Question 43

First described in 1952, is X chromosome linked, so this syndrome affects males almost exclusively.

Answer 43

Bruton’s Tyrosine Kinase (Btk) Deficiency

Question 44

Lack circulating mature CD19+ B cells and exhibit a deficiency or lack of immunoglobulins of all classes. Furthermore, they have no plasma cells in their lymphoid tissues.

Answer 44

Bruton’s Tyrosine Kinase (Btk) Deficiency

Question 45

In Bruton’s tyrosine kinase (Btk) deficiency, the patients do, however, have pre-B cells in their bone marrow. Because of the lack of B cells, _____

Answer 45

The tonsils and adenoids are small or entirely absent and lymph nodes lack normal germinal centers

Question 46

T cells are normal in number and function. About half of the patients have a family history of the syndrome.

Answer 46

Bruton’s Tyrosine Kinase (Btk) Deficiency

Question 47

They develop recurrent bacterial infections beginning in infancy as maternal antibody is cleared. The patients most commonly develop sinopulmonary infections caused by encapsulated organisms such as streptococci, meningococci, and Haemophilus influenzae.

Answer 47

Bruton’s Tyrosine Kinase (Btk) Deficiency

Question 48

Other infections frequently seen in Bruton’s Tyrosine Kinase (Btk) Deficiency

Answer 48

Bacterial otitis media, bronchitis, pneumonia, | meningitis, and dermatitis

Question 49

Some patients also have a susceptibility to certain types of viral infections, including vaccine associated poliomyelitis. In general, live virus vaccines should not be administered to immunodeficient patients

Answer 49

Bruton’s Tyrosine Kinase (Btk) Deficiency

Question 50

Results from arrested differentiation | at the pre–B-cell stage, leading to a complete absence of B cells and plasma cells.

Answer 50

X-linked hypogammaglobulinemia

Question 51

The underlying genetic mechanism of X-linked hypogammaglobulinemia

Answer 51

A deficiency of an enzyme called the Btk in B-cell progenitor cells. Lack of the enzyme apparently causes a failure of immunoglobulin VH gene rearrangement

Question 52

The syndrome can be effectively treated by administration of intramuscular or intravenous immunoglobulin preparations and vigorous antimicrobial treatment of infections.

Answer 52

X-linked hypogammaglobulinemia

Question 53

The syndrome can be differentiated from transient hypogammaglobulinemia of infancy by _____

Answer 53

the absence of CD19+ B cells in the peripheral blood, the abnormal histology of lymphoid tissues, and its persistence beyond 2 years of age.

Question 54

Immunologists have also described patients with a similar clinical presentation to Btk who have a genetic defect that is inherited in an autosomal recessive manner.

Question 55

The most common congenital immunodeficiency, occurring in about 1 in 500 persons of American or European descent

Answer 55

Selective IgA deficiency

Question 56

Most patients with a deficiency of IgA are asymptomatic. Those with symptoms usually have infections of the respiratory and gastrointestinal tract and an increased tendency to develop _______

Answer 56

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), celiac disease, and thyroiditis. Allergic disorders and malignancy are also more common

Question 57

About ___ of the IgA-deficient patients who develop infections also have an IgG2 subclass deficiency. (Selective IgA deficiency)

Answer 57

20%

Question 58

If the serum IgA is lower than 5 mg/mL,

Answer 58

The deficiency is considered severe

Question 59

If the IgA level is two SDs below the age-adjusted mean but greater than 50 mg/dL,

Answer 59

The deficiency is partial

Question 60

Although the genetic defect has not been established, it is hypothesized that lack of IgA is caused by ____

Answer 60

Impaired differentiation of lymphocytes to become IgA-producing plasma cells

Question 61

IgE antibodies specifically directed against IgA are produced by _____ of patients with severe IgA deficiency.

Answer 61

30% to 40%

Question 62

IgE antibodies specifically directed against IgA are produced by 30% to 40% of patients with severe IgA deficiency. These antibodies can cause _______

Answer 62

Anaphylactic reactions when blood products containing IgA are transfused

Question 63

Most gamma globulin preparations contain significant amounts of IgA. However, replacement IgA therapy is not useful because _____

Answer 63

The half-life of IgA is short (around 7 days) and intravenously or intramuscularly administered IgA is not transported to its normal site of secretion at mucosal surfaces. Furthermore, administration of IgA-containing products can induce the development of anti-IgA antibodies or provoke anaphylaxis in patients who already have antibodies.

Question 64

A heterogeneous group of disorders with a prevalence of about 1 in 25,000.

Answer 64

Common variable immunodeficiency (CVI)

Question 65

Although it has a low incidence (1 in 25, 000), it does make _____ the most common PID with a severe clinical syndrome

Answer 65

Common variable immunodeficiency (CVI)

Question 66

Patients usually begin to have symptoms in their 20s and 30s, but age at onset ranges from 7 to 71 years of age. The disorder can be congenital or acquired, or familial or sporadic, and it occurs with equal frequency in men and women.

Answer 66

Common variable immunodeficiency (CVI)