Implications/Analysis of Family History

An inquiry into TC’s family history revealed that no other family members had presented with these types of infections. The absence of familial presentation does not rule out an autosomal recessive disorder because both parents would need to be carriers of the defective gene. That is, both parents could be immunologically normal but each have one defective and one normal gene for the responsible gene (e.g., CD18, see later). TC would have had to inherit the two defective genes. A new mutation, however, cannot be excluded as a cause of the disorder.

Implications/Analysis of Clinical History

We need to determine why this child has prominent lesions on the skin. These areas represent places where our natural skin defense barrier is being constantly challenged by mechanical means, yet most people do not get these infections! The prevalence of bacterial infections points to defects in B cells, phagocytes, or complement. However, the lack of systemic (blood-borne) disease, such as respiratory tract infections with Pseudomonas aeruginosa or Streptococcus pneumoniae suggests this is unlikely to be a defect in the functional activity of B cells or phagocytes. The lack of viral infections suggests that this is not likely a T cell or NK cell disorder.

Implications/Analysis of Laboratory Investigation

A complete blood cell count (CBC) is a test that determines the quantity and proportion of various components in blood and includes measures of white blood cells (leukocytes), white blood cell differential, red blood cell, platelet, hemoglobin, and hematocrit (ratio of the volume of red blood cells to the volume of whole blood). A simple blood cell count measures the total white blood cell count, whereas the CBC gives, as well, a white blood cell differential that provides information regarding percentages of granulocytes, monocytes, lymphocytes, basophils, and eosinophils in the sample. A normal white blood cell count is very age dependent!!! (See Appendix.)

TC’s high normal white blood cell count and differential, with normal serum immunoglobulins, normal antibody titers to childhood immunization, and normal cytokine production by T cells should suggest that this is not likely to be a simple B cell and/or T cell disorder. Therefore, it is reasonable to conclude that TC’s infections are not due to defects in adaptive immunity. All of the information here points toward possible defects in the innate defense mechanisms. Because the CBC/differential was normal, a deficiency in any cell population of the innate immune system can be ruled out. Normal complement CH50 and AH50 tests, which measure the overall activity of the classical and alternative pathways, respectively, ruled out complement defects (see Case 11). Results of all these laboratory tests suggest the defect does not lie in a component of any effector mechanism per se.

Additional Laboratory Tests

One would certainly run some tests to make sure an unusual presentation of chronic granulomatous disease (CGD) (see Case 6) or other enzymatic defect that leads to defective macrophage resistance is not missed. CGD, associated with defects in NADPH oxidase, affects all the phagocytes in the body, wherever they might be, and so a CGD defect generally presents with frequent common multiple-site infections (e.g., the lung, upper respiratory tract). Although one might consider toll-like receptor (TLR) defects (see Case 7) or subtle nucleotide oligomerization (NOD) protein defects (see Case 9), the clinical presentations are not consistent with mutations in either of these proteins. Rather, laboratory results are consistent with the hypothesis that this child has normal effector cells that would combat infection appropriately if they were able to reach the site of infection. The defect sounds most likely to be one of altered cell migration, with the relevant effector cells not getting to the site of action. For leukocytes to leave the circulation and enter tissues at the site of infection, a number of adhesive interactions must take place between the leukocytes and the activated vascular endothelium (Fig. 8-1). A prominent molecule on leukocytes is CD18, which is known to be a component of several cell surface adhesion molecules (β2 integrins). CD18 flow cytometric analysis revealed that TC’s leukocytes did not express detectable CD18.

FIGURE 8-1 Defects in CD18 lead to a deficiency of β2 integrins on the leukocyte surface. Defects in CD18 lead to a defect in cell surface expression of β2 integrins in that they have CD18 as a component (e.g., LFA-1). Consequently, leukocytes are unable to marginate on the endothelium, a step required for diapedesis.

(Modified with permission from Gorczynski R, Stanley J: Clinical Immunology. Austin, Landes, 1999.)

Why Do Phagocytes Not Get to the Site of Infection?

It is now known that lymphoid (and other) cells of the immune system migrate within the body using discrete receptor-ligand interactions. Adhesion molecules and their ligands expressed on leukocyte cell surface (and the surface of target cells/tissue) regulate whether cells “flow” in the circulation or become arrested at certain sites (e.g., high endothelial venules) before subsequent migration into tissues. Defective genes for these “adhesion” molecules or their ligands will result in the cells being unable to adhere or undergo transmigration (through the endothelium).

Role of CD18 in Adhesion

Transmigration of leukocytes into sites of inflammation requires sequential adhesive interactions and follows a series of stages: cell rolling (selectins), firm adhesion (integrins), and transmigation (PECAMs). CD18 is the common chain of heterodimers that constitute the β2 integrin family of molecules whose role is the “firm adhesion” of leukocytes to the vascular endothelium during an inflammatory response.

CD18 pairs with different CD11 chains to form different adhesion molecules. Two of the best characterized members of the β2 integrin family are LFA-1 and Mac-1 (CD11a-CD18 and CD11b-CD18, respectively). During an inflammatory response, integrins present on different subsets of circulating leukocytes interact with their counter molecules (intercellular adhesion molecules [ICAMs]) that are upregulated on the cytokine activated vascular endothelium. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) act on the endothelium and induce the de novo expression of E-selectin and ICAM-1 on the vascular endothelium, as well as the upregulation of ICAM-2 expression.

LAD-2: Defects in Carbohydrates (Selectin Counter Molecules)

Carbohydrates present on circulating leukocytes are the counter molecules/ligands for E-selectin and P-selectin. P-selectin is the first selectin to be expressed on the endothelium during an inflammatory response because histamine (released from mast cells) triggers its translocation from the cytosol to the cell surface. Defects in fucose metabolism result in a deficiency of particular carbohydrates on the leukocyte cell surface. Because these carbohydrates are ligands for the E-selectin and P-selectin, cell rolling that should slow the leukocytes at the site of inflammation does not occur.

Wiskott-Aldrich Syndrome

Another interesting defect that can present in somewhat similar form is Wiskott-Aldrich syndrome. This is an X-linked disorder characterized by immunodeficiency, eczema, decreased numbers/function of platelets, increased susceptibility to infection, and decreased peripheral blood white cells (leukopenia).

The defect in this immunodeficiency disorder lies in the Wiskott-Aldrich syndrome protein (WASP), which plays an important role in normal actin polymerization in the cell. In addition to the pleiotropic changes just listed, mutations in WASP result in unstable actin polymerization and abnormal migration (motility defects) in monocytes/dendritic cells and lymphocytes, resulting in altered cell trafficking. A number of structurally defective WASP proteins have been described in various gene families.