Non-immunologic Causes of Increased Susceptibility to Disease

A prior post listed 7 assertions regarding the role of infectious organisms on the human genome. In the next few blogs we'll look at each assertion, in excerpts from Precision Medicine and the Reinvention of Human Disease. Here's the sixth:

Cellular defects that have no direct connection to immunity may increase susceptibility to infectious organisms.

If we want to understand why certain individuals are susceptible to infections and other individuals are not, we must understand that immune deficiencies cannot account for all infections. Infectious diseases, just like any other disease, develop in steps, and it stands to reason that there must be many different pathways through which those steps can be enhanced or blocked. Theory aside, what is the actual evidence that susceptibility to infectious diseases arise through deficiencies unrelated to the immune system?

• Time and again, we encounter serious infections from organisms thought to be nonpathogenic, occurring in immunocompetent individuals [48–51].

• Not everyone with an immune deficit will succumb to an infectious disease, implying that these individuals are protected by resistance mechanisms other than immunity.

• We know of various genetic conditions that increase our susceptibility to infectious diseases, and some of these genetic flaws have nothing to do with the adaptive (i.e., antibody-forming) immune systems. For example, children with sickle cell disease or congenital asplenia will have a heightened susceptibility to invasive pneumococcal diseases [52]. Otherwise-normal children with IRAK4 or NEMO gene mutations will also have a high risk of invasive pneumococcal disease [52]. IRAK4 or NEMO genes code for proteins involved in the phagocytosis of bacteria by splenic macrophages. Likewise, in mice, natural resistance to infection is influenced by the Bcg gene, which affects the early phagocytosis and destruction of intracellular organisms by macrophages [53]. As a final example, both humans and zebrafish that have mutations that reduce the synthesis of a proinflammatory leukotriene have heightened susceptibility to Mycobacterium tuberculosis [54]. It is easy to find examples of nonimmunologic mechanisms for susceptibility to infections [55,56].

- Jules Berman

key words: precision medicine, immune system, susceptibility to disease, non-immunologic, jules j berman Ph.D., M.D.