Primary Immunodeficiencies

A primary immunodeficiency may affect either adaptive or innate immune functions. Deficiencies involving components of adaptive immunity, such as T or B cells, are thus differentiated from immunodeficiencies in which the nonspecific mediators of innate immunity, such as phagocytes or complement, are impaired. Immunodeficiencies are conveniently categorized by the type or the developmental stage of the cells involved. Figure 19-1 reviews the overall cellular development in the immune system, showing the locations of defects that give rise to primary immunodeficiencies. As Chapter 2 explained, the two main cell lineages important to immune function are lymphoid and myeloid. Most defects that lead to immunodeficiencies affect either one or the other. The lymphoid cell disorders may affect T cells, B cells, or, in combined immunodeficiencies, both B and T cells. The myeloid cell disorders affect phagocytic function. Most of the primary immunodeficiencies are inherited, and the precise molecular variations and the genetic defects that lead to many of these dysfunctions have been determined (Table 19-1 and Figure 19-2). In addition, there are immunodeficiencies that stem from developmental defects that impair proper function of an organ of the immune system.

The consequences of primary immunodeficiency depend on the number and type of immune system components involved. Defects in components early in the hematopoietic developmental scheme affect the entire immune system. In this category is reticular dysgenesis, a stem-cell defect that affects the maturation of all leukocytes; the resulting general failure of immunity leads to susceptibility to infection by a variety of microorganisms. Without aggressive treatment, the affected individual usually dies young from severe infection. In the

VISUALIZING CONCEPTS

VISUALIZING CONCEPTS

Reticular dysgenesis

Congenital agranulocytosis

Chronic granulomatous disease

Reticular dysgenesis

Congenital agranulocytosis

Chronic granulomatous disease

Dysgenesis Reticular

Severe combined immunodeficiency

Pre-T cell

Leukocyte-adhesion deficiency

Severe combined immunodeficiency

Pre-T cell

Leukocyte-adhesion deficiency

X-linked agammaglobulinemia

Common variable hypogammaglobulinemia

X-linked hyper-IgM syndrome

Selective immunoglobulin deficiency

X-linked agammaglobulinemia

Common variable hypogammaglobulinemia

X-linked hyper-IgM syndrome

Selective immunoglobulin deficiency

Bruton Agammaglobulinemia

Bare- lymphocyte syndrome

Plasma cell

Memory B cell

DiGeorge syndrome

Bare- lymphocyte syndrome

Plasma cell

Memory B cell

FIGURE 19-1

Congenital defects that interrupt hematopoiesis ciencies, green = humoral deficiencies, red = cell-mediated defi-or impair functioning of immune-system cells result in various ciencies, and purple = combined immunodeficiencies, defects immunodeficiency diseases. (Orange boxes = phagocytic defi- that affect more than one cell lineage.)

more restricted case of defective phagocytic function, the major consequence is susceptibility to bacterial infection. Defects in more highly differentiated compartments of the immune system have consequences that are more specific and usually less severe. For example, an individual with selective IgA deficiency may enjoy a full life span, troubled only by a greater than normal susceptibility to infections of the respiratory and genitourinary tracts.

Some primary human immunodeficiency diseases and underlying genetic defects

Immunodeficiency disease

Specific defect

Impaired function

Inheritance mode*

Chromosomal defect

Severe combined immunodeficiency (SCID)

Bare lymphocyte syndrome

Wiskott-Aldrich syndrome (WAS)

Interferon gamma receptor

DiGeorge syndrome

Ataxia telangiectasia

Gammaglobulinemias

Chronic granulomatous disease

Chediak-Higashi syndrome Leukocyte-adhesion defect

RAG-1/RAG-2 deficiency

ADA deficiency 1

PNP deficiency I

JAK-3 deficiency 1

IL-2Ry-deficiency J

ZAP-70 deficiency

Defect in MHC class II gene promoter

Cytoskeletal protein (CD43)

IFN-y-receptor defect

Thymic aplasia

Defective cell-cycle kinase

X-linked agammaglobulinemia

X-linked hyper-IgM syndrome

Common variable immunodeficiency

Selective IgA deficiency

Cyt p91phox

Cyt p67phox

Cyt p22phox

Defective intracellular transport protein (LYST)

Defective integrin ß2 (CD18)

No TCR or Ig gene rearrangement

Toxic metabolite in T and B cells

Defective signals from IL-2,4, 7,9,15,

Defective signal from TCR

No class II MHC molecules

Defective T cells and platelets

Impaired immunity to mycobacteria

T- and B-cell development

Low IgA, IgE

Bruton's tyrosine kinase (Btk); no mature B cells

Defective CD40 ligand

Low IgG, IgA; variable IgM

Low or no IgA

No oxidative burst for bacterial killing

Inability to lyse bacteria

Leukocyte extravasation

AR AR

AR XL

AD AR XL

XL AR AR

11 p13

20q13 14q13

19p13 Xq13

2q12

16p13

Xp11

6q23

22q11 11 q22 Xq21

Xq26

Complex Complex

Xp21 1q25 16q24

1q42 21q22

*AR = autosomal recessive; AD = autosomal dominant; XL = X linked; "Complex" indicates conditions for which precise genetic data are not available and that may involve several interacting loci.

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Responses

  • mike egger
    Have Reticular Dysgenesis?
    7 years ago
  • Joann
    How does genetic abnormality give rise to reticular dysgenesis?
    7 years ago
  • janie
    How does reticular dysgenesis affect cell function?
    7 years ago

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