Rapid induction of autoantibodies during ARDS and septic shock
© Burbelo et al; licensee BioMed Central Ltd. 2010
Received: 10 September 2010
Accepted: 14 October 2010
Published: 14 October 2010
Little is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS) and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction.
Using Luciferase Immunoprecipitation Systems (LIPS), a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time.
From screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected.
The rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins.
Serum antibodies are essential components of adaptive immunity, but are also involved in the pathogenesis of many autoimmune diseases. While much is known about the control of host antibody production following pathogen exposure or vaccination , the induction of autoantibodies in human autoimmune and other diseases remains poorly defined. In genetically susceptible individuals, infection and other environmental insults have been speculated to trigger immune responses by different mechanisms including induction of cytokines, stimulation of toll-like receptors and other pattern recognition receptors, the release of self antigens by damaged cells and tissues and/or molecular mimicry . However to date, little is known about the spectrum of autoantibody responses and the kinetics of autoantibody induction during acute infection and systemic inflammation.
Acute respiratory distress syndrome (ARDS) and severe sepsis are acute inflammatory conditions associated with high morbidity and mortality, often involving multiple organ failure [3, 4]. ARDS is caused by a wide variety of infectious or inflammatory insults to the lung that may occur by direct (e.g. pneumonia) or indirect injury (e.g. peritonitis). The pathologic hallmarks of ARDS are diffuse alveolar damage manifested by disruption of the alveolar-capillary interface, as well as the accumulation of inflammatory cells and protein-rich exudates in the alveolar spaces . Patients with ARDS have elevated levels of inflammatory mediators such as TNF-α, IL-1β, IL-6 and IL-8 in lung lining fluid as well as in the circulation . In sepsis a nidus of infection causes a local and systemic inflammatory response . However as sepsis persists, there is a rapid shift towards an anti-inflammatory immunosuppressive state that likely involves T-cell anergy [6, 7], increased anti-inflammatory cytokines  and the loss of dendritic cells, B lymphocytes and CD4+ T lymphocytes [9, 10].
Luciferase immunoprecipitation systems (LIPS), offers a highly quantitative and sensitive method to measure antibody responses against large numbers of foreign antigens and autoantigens [11–16]. In this study, LIPS was used to profile plasma from patients with ARDS or sepsis against a panel of known autoantigens. Within 10 to 14 days after the onset of illness, nearly 50% of the patients show high antibody titers to at least one autoantigen. Remarkably, analysis of serial samples revealed that the induction of these autoantibodies occurred rapidly, often within 1-7 days after intensive care unit admission and in some cases remained elevated for several weeks. The mechanisms and time course for the rapid induction of autoantibodies seen in ARDS and sepsis may occur in other conditions including autoimmune diseases.
Clinical Characteristics Based on Autoantibody Status
Autoantibody Positive a (n = 20)
Autoantibody Negative a (n = 15)
Age yrs (mean ± SD)
45 ± 14
52 ± 16
8 male (40%)
10 male (67%)
APACHE 3 score (mean ± SD)
58 ± 17
62 ± 16
Methylprednisolone treatment b
Gram positive bacteria: 12
Gram negative bacteria: 3
Culture negative: 5
Gram positive bacteria: 4
Gram negative Bacteria: 7
Culture negative: 2
Autoantibody Positive a (n = 6)
Autoantibody Negative a (n = 7)
Age yrs (mean ± SD)
54 ± 21
63 ± 18
5 male (83%)
7 male (100%)
APACHE 3 score (mean ± SD)
75 ± 26
68 ± 23
Hydrocortisone treatment c
Gram positive bacteria: 6
Gram negative bacteria: 0
Gram positive bacteria: 3
Gram negative bacteria: 4
Ruc-antigen fusions and LIPS analysis
Many of the autoantigens used in these LIPS studies including those for glutamic decarboxylase-65 (GAD65), AQP-4, gastric ATPase and a fragment of Ro52 (Ro52-Δ2) have been previously described [14–16]. Four cytokines (Interferon-γ, Interferon-ω, Interleukin-6 and interleukin-1α) corresponding to the processed cytokine missing the signal peptide sequences were also generated as C-terminal Ruc-antigen fusions . In addition a new lung autoantigen, KCNRG and four other cytokines were constructed as C-terminal antigen fusions downstream of Renilla luciferase (Ruc) using the pREN2 vector . DNA sequencing was used to ensure the integrity of this new construct.
LIPS assay was performed at room temperature as described . In these assays, sera were processed in a 96-well format. A "master plate" was first constructed by diluting patient sera 1:10 in assay buffer A (50 mM Tris, pH 7.5, 100 mM NaCl, 5 mM MgCl2, 1% Triton X-100) in a 96-well polypropylene microtiter plate. For evaluating antibody titers by LIPS, 40 μl of buffer A, 10 μl of diluted human sera (1 μl equivalent), and 1 × 107 light units (LU) of Ruc-antigen Cos1 cell extract, diluted in buffer A to a volume of 50 μl, were added to each well of a polypropylene plate and incubated for 60 minutes at room temperature on a rotary shaker. Next, 5 μl of a 30% suspension of Ultralink protein A/G beads (Pierce Biotechnology, Rockford, IL) in PBS were added to the bottom of each well of a 96-well filter HTS plate (Millipore, Bedford, MA). To this filter plate, the 100 μl antigen-antibody reaction mixture was transferred and incubated for 60 minutes at room temperature on a rotary shaker. The washing steps of the retained protein A/G beads were performed on a Tecan plate washer with a vacuum manifold. After the final wash, LU were measured in a Berthold LB 960 Centro microplate luminometer (Berthold Technologies, Bad Wilbad, Germany) using coelenterazine substrate mix (Promega, Madison, WI). All light unit (LU) data were obtained from the average of two separate experiments and not corrected for negligible background protein A/G bead binding. Patient samples positive at day 10 for ARDS or day 14 for sepsis were reexamined for changes in antibody titers using all available serial samples.
GraphPad Prism software (San Diego, CA) was used for statistical analysis. Due to the overdispersed nature of the autoantibody titers, the healthy control subjects (CTRL) are reported as the geometric mean titer (GMT) ± 95% confidence interval. For determining the cut-off limits for each of the LIPS tests, the mean value of the 24 control samples plus 3 standard deviations (SD) in the first cohort was used and is indicated in the figures. The non-parametric Mann-Whitney U test was used for comparison of antibody titers in different groups. Using contingency tables, the Fischer's exact test was used to determine the statistical significance between autoantibody seropositivity and in-hospital survival.
Data transformation and a heatmap were used to visualize the autoantibody profiles of the participants as a single graphic. In order to create this heatmap, the mean and standard deviation of the antibody titers for each antigen in the 24 control samples was first generated as a reference scale. Next, antibody titer values for each antigen-antibody measurement greater than the control mean plus 3 SD were color-coded to signify the relative number of standard deviations above these cut-off values. Lastly, the samples were rank ordered with respect to anti-KCNRG autoantibodies, the most informative autoantigen in the ARDS and sepsis patients.
Detection of high titer autoantibodies to proinflammatory cytokines in selected ARDS and sepsis patients
Detection of immunoreactivity to diverse autoantigen targets in ARDS and sepsis
In light of detecting anti-cytokine autoantibodies in both ARDS and sepsis patients, other potential autoantigens were also evaluated. Since we hypothesized that ARDS and septic patients might show immunoreactivity with antigens derived from damaged tissue and organs, we tested a panel of known autoantigens associated with several autoimmune diseases. The autoantigens Jo-1, MuSK, and La failed to show any statistically significant responses in both patients with ARDS and those with severe sepsis (data not shown). From screening several other autoantigens, we detected autoantibodies against the lung-specific autoantigen potassium channel regulator (KCNRG). Although the anti-KCNRG autoantibody titers were modestly elevated compared to the anti-cytokine autoantibodies, 23% (8/35) of the ARDS and 25% (3/12) of the sepsis patients had statistically significant autoantibody titers that were higher than the control cut-off (Figure 1E). Mann Whitney U test analysis revealed significantly higher detectable anti-KCNRG autoantibody titers in both the ARDS (P < 0.006) and sepsis patient groups (P < 0.03) compared to the controls (Figure 1E). These results suggest that the KCNRG protein is a target of autoantibodies in patients with ARDS and sepsis.
Screening of several other autoantigens, including gastric ATPase, GAD65, AQP-4 and Ro52 also revealed high titer autoantibodies in several patients from the ARDS and severe sepsis cohorts. For example, elevated anti-gastric ATPase autoantibodies, higher than the cut-off derived from the controls, were found in 14% of the ARDS patients (5/35) as well as one patient with severe sepsis (Figure 1F). Testing for anti-AQP-4 antibodies revealed that 9% (3/35) of the ARDS and 15% (2/13) of sepsis samples had antibody titers above the cut-off value of the mean plus 3 SD of the 24 control samples (Figure 1G). High titer autoantibodies above the control cut-off were also detected to GAD65 in three ARDS and two sepsis patients (data not shown). Lastly, one ARDS and one sepsis patient had statistically significant levels of autoantibodies to Ro52 (Figure 1H). Together, these results suggest that ARDS and sepsis patients have a high frequency of autoantibodies against a number of diverse autoantigen targets that are classically associated with several different autoimmune conditions.
Autoantibody profiles in ARDS and sepsis
Since only 57% of ARDS and 46% of septic patients demonstrated at least one statistically significant elevated autoantibody compared to the controls, at present it is difficult to make any general conclusions about the predictive value of these autoantibodies for determining severity. However, the relationship between short-term survival and autoantibodies was examined. As shown in Table 1, the ARDS autoantibody positive patients showed a 90% (18/20) in-hospital survival rate, while the autoantibody negative samples showed a 60% survival rate (9/15). Similarly, the autoantibody positive sepsis patients showed a 67% (4/6) survival rate and the autoantibody negative sepsis patients had a 71% (5/7) survival rate. Statistical analysis using Fischer's exact tests did not reveal any significant differences between the different groups. Lastly, this study with short-term samples from ARDS and sepsis patients was not designed to analyze the significance of these autoantibodies as they relate to long-term morbidity and mortality.
Kinetics of autoantibody induction in ARDS and sepsis
Our findings document the relatively high prevalence of autoantibodies in acute, inflammatory, high mortality conditions of ARDS and severe sepsis. The high detection rate of autoantibodies, 57% in ARDS and 46% in severe sepsis patients using a relatively small panel of autoantigens, suggests that the observed immunoreactivity to self proteins is a relatively common phenomenon in these two conditions. The most frequent autoantigen target in ARDS and sepsis was KCNRG, a protein highly expressed in the lung . While autoantibodies to KCNRG have only been previously reported in a subset of autoimmune polyendocrine syndrome patients with lung complications , our finding of anti-KCNRG autoantibodies in ARDS and sepsis patients is consistent with the pulmonary injury and tissue destruction associated with these conditions. The detection of autoantibodies to the gastric ATPase autoantigen, a frequent target in a number of autoimmune conditions including autoimmune gastritis , type I diabetes  and Sjögren's syndrome , suggests that the stomach may be a highly promiscuous target of autoantibody attack in diverse inflammatory and autoimmune conditions. It should also be noted that many of the patients were concurrently on corticosteroids, but did not appear to block autoantibody production. The finding of the rapid induction of autoantibodies against the Ro52 autoantigen, one of the major rheumatological antigens comprising the SSA test, may coincide with the massive increase in antibodies directed at potential pathogens and human autoantigens that occur during ARDS and sepsis. Recent studies suggest that Ro52 autoantigen plays an important role in quality control of misfolded immunoglobulins produced by B-lymphocytes  and may be released from dying lymphocytes and other cells.
Consistent with the intense host inflammatory response found in ARDS (5) and sepsis , high titer autoantibodies were detected to a number of cytokines including IL-6, interferon-ω, interferon-γ and interleukin-1-α. In contrast to a previous report , we were unable to detect autoantibodies to IL-8 in any of the samples. Nevertheless, the finding that some patients show autoantibodies to a number of cytokines suggests that these antibodies may be biomarkers for the high levels of cytokines which may cause autoimmunization and possibly contribute to immune dysfunction seen in ARDS and sepsis. Alternatively these autoantibodies may play a role patient susceptibility to opportunistic infection. For example, anti-INF-γ autoantibodies are found in patients with susceptibility to non-tuberculosis mycobacterium infection [25–27], anti-IL-6 has been reported in a patient with chronic skin infection , and a variety of anti-cytokine autoantibodies are detected in a subset of thymoma patients with opportunistic infections [18, 29, 30]. Interestingly, 1 sepsis and 3 ARDS patients had relatively high titer autoantibodies against IL-6 and/or INF-ω suggesting that these autoantibodies might have a role in dampening the activity of these cytokines. Future investigations using other bioassays, such as looking for cytokine neutralizing activity, are necessary to further understand the functional significance of anti-cytokine autoantibodies in ARDS and sepsis.
Many of the autoantibody responses detected in ARDS and severe sepsis patients showed dynamic responses and marked changes in titer over a short period of time. Overall the findings of the rapid induction of autoantibodies against one or several autoantigen targets in the same patients do not support a role of molecular mimicry in inducing these antibodies. The mechanism for the rapid production of autoantibodies is intriguing. Long-term memory B-cells which are responsible for the extraordinary longevity of human serological memory  may also be involved in the rapid synthesis of autoantibodies described here. Rather than the long-term memory B-cells directed against pathogen proteins, small numbers of memory B-cells directed against self proteins may be present in all humans, but in most cases remain dormant. Following re-exposure to these self-antigens from tissue destruction and/or other antigen-independent mechanism including activation of cytokines and toll receptors, these memory B-cells may expand and differentiate into autoantibody producing plasma cells. Consistent with this notion is the finding that many of the autoantibody titers peaked at days 7-14 which may correlate with the time frame needed to induce these autoantibodies after the start of the inflammatory host response. Lastly, the time course for the rapid induction of autoantibodies seen in ARDS and sepsis may occur in other conditions including autoimmune diseases.
Although this study focused on short-term outcomes, it is intriguing that at these early time points autoantibodies associated with neurological targets are detected. There is evidence suggesting that ARDS patients suffer long-term adverse neuromuscular sequelae , and it is possible that autoantibodies and T-cell-mediated autoimmunity might contribute to these problems at later time points. For example, the presence of autoantibodies against AQP-4 and GAD65 in some ARDS and sepsis patients may be related to long-term neurological deficits seen in these patients. Anti-AQP-4 autoantibodies are found in patients with neurological complications including autoimmune attack on the optic nerve, spinal cord and peripheral nerves [16, 33, 34]. Anti-GAD65 autoantibodies have also been reported in a number of different neurological diseases including Stiff person syndrome, encephalitis and epilepsy, as well as being the major autoantigen in type I diabetes . It is possible that the anti-AQP-4 and anti-GAD65 autoantibodies reflect autoimmune attack on the nervous system triggered by these conditions. Consistent with this possibility, it is interesting to note that some of autoantibodies detected in ARDS including to KCNRG, AQP-4 and GAD65, show sustained elevation past the last collected plasma samples at day 20 to 28. Since we were unable to analyze long-term outcome of these patients, it is unclear whether the presence of these autoantibodies are associated with long-term sequelae of critical illness. It is also unclear whether subsequent mild infections, inflammation and other trauma might reactivate autoantibody production at a later time in certain seropositive patients. Future studies expanding the autoantigen panel, profiling later time points and attempting to correlate autoantibody elevation with relevant clinical outcomes are needed to understand whether these autoantibodies have pathophysiological consequences.
The authors thank the patients who volunteered for these studies. This work was supported by in part by the Intramural Research Program of the NIH, the National Institute of Dental and Craniofacial Research, the NIH Clinical Center and in part a grant from the Biomarker subsection of the Center for Neuroscience and Regenerative Medicine.
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