Simultaneous disseminated infections with intracellular pathogens: an intriguing case report of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

Abstract Background Severe and disseminated non-tuberculous mycobacterial (NTM) infections are frequently linked to a genetic predisposition but acquired defects of the interferon gamma (IFNγ) / interleukin 12 (IL-12) pathway need to be considered in adult patients with persistent or recurrent infections. Neutralizing anti-IFNγ autoantibodies disrupting IFNγ signalling have been identified as the cause of a severe and unique acquired immunodeficiency syndrome with increased susceptibility to NTM and other intracellular pathogens. Case presentation An adult Asian female with a previous history of recurrent NTM infections presented with persistent diarrhea, abdominal pain, night sweats and weight loss. Severe colitis due to a simultaneous infection with cytomegalovirus (CMV) and Salmonella typhimurium was diagnosed, with both pathogens also detectable in blood samples. Imaging studies further revealed thoracic as well as abdominal lymphadenopathy and a disseminated Mycobacterium intracellulare infection was diagnosed after a lymph node biopsy. Further diagnostics revealed the presence of high-titer neutralizing anti-IFNγ autoantibodies, allowing for the diagnosis of adult-onset immunodeficiency with anti-IFNγ autoantibodies (AIIA). Conclusions We here present a severe case of acquired immunodeficiency with anti-IFNγ autoantibodies with simultaneous, disseminated infections with both viral and microbial pathogens. The case illustrates how the diagnosis can cause considerable difficulties and is often delayed due to unusual presentations. Histological studies in our patient give further insight into the pathophysiological significance of impaired IFNγ signalling. B-cell-depleting therapy with rituximab offers a targeted treatment approach in AIIA.

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Co-infection of macrophages modulates interferon gamma and tumor necrosis factor-induced activation against intracellular pathogens.

Journal of Experimental Medicine ◽

10.1084/jem.172.3.977 ◽

1990 ◽

Vol 172 (3) ◽

pp. 977-980 ◽

Cited By ~ 23

Author(s):

C M Black ◽

L E Bermudez ◽

L S Young ◽

J S Remington

Keyword(s):

Interferon Gamma ◽

Mononuclear Phagocytes ◽

Intracellular Pathogens ◽

Inhibition Of Growth ◽

Static Activity ◽

Acquired Immunodeficiency ◽

Mycobacterium Avium Intracellulare ◽

Cytokine Stimulation ◽

Immunodeficiency Syndrome ◽

Necrosis Factor

Co-infection of macrophages (M phi) with Toxoplasma gondii and Mycobacterium avium-intracellulare complex (MAC) has been observed in patients with acquired immunodeficiency syndrome (AIDS). In this study we have demonstrated that co-infected murine M phi respond differently to cytokine stimulation than M phi infected with either of the microorganisms alone. Whereas treatment with interferon gamma (IFN-gamma) activated both single and co-infected groups of M phi to kill T. gondii, treatment with TNF did not influence the rate of MAC growth in co-infected M phi, in contrast with the inhibition of growth observed in MAC-infected M phi. These results suggest that in AIDS patients suffering infection with multiple intracellular pathogens, the ability of cytokines to stimulate microbicidal or static activity in mononuclear phagocytes can be impaired by the presence of more than one of the intracellular organisms.

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Faculty Opinions recommendation of Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005680.67205 ◽

2002 ◽

Author(s):

John Moore

Keyword(s):

Virus Infection ◽

Interferon Gamma ◽

Acquired Immunodeficiency Syndrome ◽

Rhesus Macaques ◽

Lymphoid Tissues ◽

Immunodeficiency Virus ◽

Cxc Chemokine ◽

Chemokine Ligand ◽

Acquired Immunodeficiency ◽

Immunodeficiency Syndrome

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Faculty Opinions recommendation of The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1099170.555385 ◽

2008 ◽

Author(s):

Rachel R Caspi

Keyword(s):

T Cells ◽

Transcription Factor ◽

Interferon Gamma ◽

Cd4 T Cells ◽

Interleukin 12 ◽

Th 17 ◽

Signaling Axis

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Type 1 Immunity Provides Optimal Protection against Both Mucosal and Systemic Trypanosoma cruzi Challenges

Infection and Immunity ◽

10.1128/iai.70.12.6715-6725.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6715-6725 ◽

Cited By ~ 38

Author(s):

D. F. Hoft ◽

C. S. Eickhoff

Keyword(s):

Trypanosoma Cruzi ◽

Neutralizing Antibody ◽

Secretory Iga ◽

Immune Memory ◽

Interleukin 12 ◽

Intracellular Pathogens ◽

Protective Effects ◽

Culture Techniques

ABSTRACT Chagas' disease results from infection with Trypanosoma cruzi, a protozoan parasite that establishes systemic intracellular infection after mucosal invasion. We hypothesized that ideal vaccines for mucosally invasive, intracellular pathogens like T. cruzi should induce mucosal type 2 immunity for optimal induction of protective secretory immunoglobulin A (IgA) and systemic type 1 immunity protective against intracellular replication. However, differential mucosal and systemic immune memory could be difficult to induce because of reciprocal inhibitory actions between type 1 and type 2 responses. To test our hypotheses, we investigated the protective effects of type 1 and type 2 biased vaccines against mucosal and systemic T. cruzi challenges. Intranasal vaccinations were given with recombinant interleukin-12 (IL-12)- and IL-4-neutralizing antibody (Ab) for type 1 immune bias, or recombinant IL-4 and gamma interferon-neutralizing Ab for type 2 immune bias. Cytokine RNA and protein studies confirmed that highly polarized memory immune responses were induced by our vaccination protocols. Survival after virulent subcutaneous T. cruzi challenge was used to assess systemic protection. Mucosal protection was assessed by measuring the relative inhibition of parasite replication in mucosal tissues early after oral T. cruzi challenge, using both PCR and quantitative culture techniques. As expected, only type 1 responses protected against systemic challenges (P < 0.01). However, contrary to our original hypothesis, type 1 responses optimally protected against mucosal challenges as well (P < 0.05). Type 1 and type 2 biased vaccines induced similar secretory IgA responses. We conclude that future vaccines for T. cruzi and possibly other mucosally invasive, intracellular pathogens should induce both mucosal and systemic type 1 immunity.

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Interleukin-12 augments a Th1-type immune response manifested as lymphocyte proliferation and interferon gamma production in Leishmania infantum-infected dogs

International Journal for Parasitology ◽

10.1016/j.ijpara.2004.10.015 ◽

2005 ◽

Vol 35 (1) ◽

pp. 63-73 ◽

Cited By ~ 38

Author(s):

Dalit Strauss-Ayali ◽

Gad Baneth ◽

Sharon Shor ◽

Fumiyoshi Okano ◽

Charles L. Jaffe

Keyword(s):

Immune Response ◽

Interferon Gamma ◽

Leishmania Infantum ◽

Lymphocyte Proliferation ◽

Interleukin 12

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HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies

PLoS ONE ◽

10.1371/journal.pone.0128481 ◽

2015 ◽

Vol 10 (5) ◽

pp. e0128481 ◽

Cited By ~ 13

Author(s):

Manop Pithukpakorn ◽

Ekkapong Roothumnong ◽

Nasikarn Angkasekwinai ◽

Bhoom Suktitipat ◽

Anunchai Assawamakin ◽

...

Keyword(s):

Interferon Gamma ◽

Adult Onset

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Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1273 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1273-1283 ◽

Cited By ~ 269

Author(s):

R Manetti ◽

F Gerosa ◽

M G Giudizi ◽

R Biagiotti ◽

P Parronchi ◽

...

Keyword(s):

T Cells ◽

Interferon Gamma ◽

Specific Antigen ◽

Th2 Cells ◽

Interleukin 12 ◽

T Helper ◽

Ifn Gamma ◽

Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

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