Ontogeny of Th1 Memory Responses against aBrucella abortusConjugate

Abstract

Protective immune responses to intracellular pathogens such as Brucella abortus are characteristically Th1-like. Recently we demonstrated that heat-killed B. abortus (HKBa), a strong Th1 stimulus, conjugated to ovalbumin (HKBA-OVA), but not B. abortus alone, can alter the antigen-specific cytokine profile from Th2-to Th1-like. In this report we study the ability of a single injection of B. abortus to switch a Th2 to a Th1 response in immature mice. One-day-and 1-week-old mice were given a single injection of B. abortus in the absence or presence of OVA, and at maturity mice were challenged with an allergenic preparation, OVA with alum (OVA-A). B. abortus given without OVA did not diminish the subsequent Th2 response in either age group. In contrast, mice receiving a single injection of B. abortus-OVA at the age of 1 week, but not those injected at the age of 1 day, had reversal of the ratio of OVA-specific Th1 to Th2 cells and decreased immunoglobulin E levels after allergen challenge as adults. Within 6 h both 1-day-and 1-week-old mice expressed interleukin-12 p40 mRNA following either B. abortus or B. abortus-OVA administration. However, only the 1-week-old mice exhibited increased expression of gamma interferon (IFN-␥) mRNA. The absence of the early IFN-␥ response in 1-day-old mice may explain their inability to generate a Th1 memory response. These results suggest that at early stages of immune development, responses to intracellular bacteria may be Th2-rather than Th1-like. Furthermore, they suggest that the first encounter with antigen evokes either a Th1-or a Th2-like response which becomes imprinted, so that subsequent memory responses conform to the original Th bias. This has implications for protection against infectious agents and development of allergic responses.

Ex Vivo Innate Immune Cytokine Signature of Enhanced Risk of Relapsing Brucellosis

“…are intracellular pathogens whose effective control and elimination requires a potent cell-mediated Th1 immune response [9], [21], [22]. We found that relapse brucellosis patients demonstrated higher basal IL-1β and GM-CSF gene expression compared to control donors, increased IFN-γ expression after heat-killed B. melitensis (HKBM) stimulation and higher TNF-α expression after LPS stimulation compared to both acute brucellosis patients and control donors.…”

Dominant Th1 cytokine production in early onset of human brucellosis followed by switching towards Th2 along prolongation of disease

“…10 It is also documented that IL-4 is able to down-regulate the secretion of IFN-g by CD4 þ T cells and cause exacerbation of B. abortus infection. 11,12 Despite the huge body of evidence regarding the role of different cytokines in the course of brucellosis in mice, there are a limited number of observations on humans. It has been shown that the serum level of IL-12 and IFN-g are elevated during the course of brucellosis.…”

An Autoimmune Disease-Associated Risk Variant in the TNFAIP3 Gene Plays a Protective Role in Brucellosis That Is Mediated by the NF-κB Signaling Pathway

“…IL-10 is a cytokine synthesis inhibitory factor because of its negative regulatory effect on cytokines, specifically IL-2 and gamma interferon (IFN-γ). In a murine model, IL-10 has been shown to influence the development of brucellosis by downregulating the response of CD4 + T helper cells and the secretion of IFN-γ ( 43 , 44 ). On the other hand, IL-10 also promotes B cell antibody production.…”