Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies—(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)—to a newer approach—(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models. Whereas DMARDs ablate or inhibit specific proinflammatory cytokines or cells and jakinibs inhibit the receptor activation cascade for expression of proinflammatory cytokines, the LEAPS therapeutic vaccines specifically modulate the ongoing antigen-specific, disease-driving, proinflammatory T memory cell responses. This decreases disease presentation and changes the cytokine conversation to decrease the expression of inflammatory cytokines (IL-17, IL-1(α or β), IL-6, IFN-γ, TNF-α) while increasing the expression of regulatory cytokines (IL-4, IL-10, TGF-β). This review refocuses the purpose of therapy for RA towards rebalancing the immune system rather than compromising specific components to stop disease. This review is intended to be thought provoking and look forward towards new therapeutic modalities rather than present a final definitive report.

The presentation of an infectious disease in a child is likely to differ from an adult and will differ at different ages of the child. In addition to differences in immune response, there are significant differences in anatomy, physiology, metabolism, and behavior that affect susceptibility, course of disease, severity, and treatment. This is the first of a series of reviews that examine differences in disease presentation for different demographics. This short review will look at some of the parameters that ask, “Why is a child not a miniadult for infections?”

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) induced both therapy and antibodies. Spleen T cells from GIA mice, vaccinated with the DerG LEAPS peptides, preferentially produced anti-inflammatory (IL-4 and IL-10) rather than pro-inflammatory (IFN-γ or IL-17) cytokines in culture. Similarly, cytokines secreted by CD4+ cells of unvaccinated GIA mice, differentiated in vitro to Th2 cells and treated with either or both DerG vaccine peptides, exhibited an anti-inflammatory (IL-4, IL-10) profile. These results suggest that the two peptides elicit different therapeutic immune responses by the immunomodulation of disease-promoting pro-inflammatory responses and that the combination of the two LEAPS conjugates may provide broader epitope coverage and, in some cases, greater efficacy than either conjugate alone.

The components of the immune system develop in utero and like a computer, some components are immediately functional (the innate components) but other components must learn the programs and details necessary to function (antigen adaptive components). Like other systems, including military and municipal, the innate and antigen specific components develop into an immune system that helps maintain and surveil the other body processes and systems for aberrations, provide surveillance and protection of the mucoepithelial borders and protection from microbial invasion. Inability, excesses, or errors in these processes cause disease. Aging of the immune system brings immunosenescence, inflammaging, more errors, and decreased surveillance which increases risk for new infections (e.g. COVID-19, influenza), recurrence of latent infections, cancer and autoimmune and inflammatory diseases. With greater understanding of the surveillance, effector and regulatory deficits upon aging, better therapies can be developed.

Monoclonal antibodies (mabs) and small molecule Janus kinase (JAK) inhibitors (nibs) are useful for treating inflammatory disease, autoimmune disease, and tumors, especially leukemia. Inhibition or depletion of the cytokines or cells with these drugs can result in loss of important protection against certain microbial infections. Recurrences of tuberculosis, hepatitis B and C, and zoster are especially sensitive to immune depletion. The consequences of inhibition of cytokines, molecules, pathways and cells by these drugs are described, depicted, and tabulated.

Much of COVID-19 disease can be attributed to the stable structure of the envelope, which facilitates its transmission; the spike protein and its receptor which determine which tissues get infected and are susceptible to viral and immune cytolysis; and evasion of initiation of type 1 and 3 interferons, which gives the virus a replicative head start and ability to spread while simultaneously compromising the antiviral immune response.