Ignite Creation Date:
2024-05-06 @ 8:04 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06248957
Status:
RECRUITING
Last Update Posted:
2024-02-08
First Post:
2024-01-31
Brief Title:
SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
Sponsor:
Karolinska Institutet
Organization:
Karolinska Institutet
Study Overview
Official Title:
SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
Status:
RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SAID
Brief Summary:
The aim of the SAID study is to create a national resource in Sweden to enable comprehensive immunological analyses of an extremely complex and clinically challenging group of individuals with variable forms of immune system dysregulation We hope to establish a biobank of primarily blood and fecal samples from children and adults with confirmed or suspected immune dysregulation as well as age- and sex- matched healthy controls for comparisons of immune cellmediator alongside various clinical presentations of these immunological diseases as well as microbiome samples as possible a possible modifier of clinical presentations The project will also include the establishment of a national database with deep immunological data treatment and clinical outcomes for these patients accessible to participating researchers and clinicians
Detailed Description:
BACKGROUND
Immune dysregulation encompasses multiple different conditions in which the immune system does not function properly and displays inappropriate or inadequate responses overreactions or under-reactions directed towards external or internal targets It is a broad term and its manifestations include several different categories of disease
Immunodeficiencies These disorders impair the immune systems ability to defend the body against foreign or abnormal cells that invade or attack it such as bacteria viruses fungi and cancer cells As a result unusual bacterial viral or fungal infections or lymphomas or other cancers may develop Primary immunodeficiencies PIDs comprise a group of nearly 500 inherited disorders often due to single-gene mutations that result in the specific impairments in immune function Secondary immunodeficiencies SIDs involve a weakened immune system caused by external sources eg chemical chemotherapy infection HIV or cancer
Autoimmune Disorders In these conditions the production of autoantibodies against self-antigens causes the immune system to attack healthy cells and tissues Some of the most common examples include type 1 diabetes T1D rheumatoid arthritis RA multiple sclerosis MS systemic lupus erythematosus SLE
Autoinflammatory Disorders Here dysregulation of the innate immune system leads to spontaneous and recurrent inflammatory episodes In contrast to autoimmune diseases where antibodies against self-antigens play a central role the defect in autoinflammatory diseases often lies in the first responder innate arm of the immune system where the defect triggers inappropriate activation of the normal inflammatory response or disables resolution thereof Examples include familial Mediterranean fever FMF and cryopyrin-associated periodic syndromes
Severe allergies Allergic reactions are misdirected reactions of the immune system to substances commonly found in the environment Allergens elicit a T helper 2 immune response including the involvement of IgE mast cells innate lymphoid cells 2 ILC2 eosinophils and basophils Severe Allergy which does not respond to therapy can also indicate underlying immundysregulation
Lymphoproliferation Lymphoproliferation LP refers to persistent polyclonal oligoclonal or monoclonal proliferation of lymphoid cells in the clinical setting of immune dysregulation Symptoms are non-specific and mimic those of an infection inflammation or neoplasia and are characterized by chronic or recurrent lymphadenopathy hepatosplenomegaly extranodal infiltration andor peripheral blood lymphocytosis Immune disorders characterized by LP include autoimmune lymphoproliferative syndrome ALPS and X-linked lymphoproliferation XLP
Attempting to classify and group disorders of immune dysregulation in this way is of course an over-simplification as exemplified by conditions with both autoimmune and autoinflammatory components such as psoriasis or IBD For this reason it has been proposed that manifestations of immune dysregulation should be considered as a continuum with rare monogenic autoimmune disorders at one end rare monogenic autoinflammatory disorders at the other end followed by polygenic autoimmuneautoinflammatory conditions respectively with mixed pattern diseases in the center In real life patients with immune dysregulation also often present with more than one disease manifestation which further complicates diagnosis and treatment
Finally another factor that must be considered when trying to understand immune dysregulation is the influence of the microbiome Disruptions to the microbiota early in life are known to have lasting health effects including increased risks of immune- mediated diseases such as allergy However less is known about the possibility that inborn errors of immunity may also shape the developing microbiome with ensuing health-related consequences although the role of the microbiome in immune dysfunction is beginning to be appreciated For example impaired immunity may alter the intestinal microbiome causing subsequent increased intestinal permeability with increased exposure to bacterial DNA and an activation of innate and adaptive immune that ultimately perpetuate or exacerbate any defects in immunity
THE PROBLEM Certain types of immune dysregulation can be extremely rare and diagnosis and appropriate treatment are complicated issues Some are caused by specific genetic mutations with on average one new genetic mutation associated with immune dysregulation being discovered every month However in over half of patients with eg autoinflammatory disorders no genetic cause can be found Some disorders also affect multiple branches of the immune system due to a broader inappropriate immune response where signs and symptoms of autoimmunity allergy andor immunodeficiency can all be present in one condition at the same time A new approach is therefore essential to facilitate diagnosis and personalized treatment of patients with immune dysregulation which we believe will involve more holistic systems-level analyses of immune cell composition and functional responses Furthermore little is known about the interaction between the immune function and microbiome composition particularly in relation to immune dysregulation and understanding this interplay may reveal new therapeutic opportunities and enable prediction of adverse outcomes
SYSTEMS IMMUNOLOGY The human immune system consists of many specialized cell populations that stimulate each other to respond but also compete for growth factors and directly suppress each other to prevent immune pathology In this way the whole system functions as a highly integrated network Since this network is decentralized without any master regulator all actions in the system both productive immune responses to microbes and destructive autoimmune attacks on normal tissues emerge from the combined actions of the many immune cell populations that make up this network To understand higher order functions in a system this complex comprehensive analyses involving all cell populations simultaneously are required Only then can the consequence of activating one or a few specific cell populations in the system as a whole be understood This realization has led to the pursuit of Systems Immunology the application of technologies and theories from the field of Systems Biology to understand immune systems Technological advances primarily in mass cytometry for high- dimensional immune cell analysis and high-throughput serum protein analyses now allow for such detailed profiling of all components that make up human immune systems We therefore now have the ability to dissect immune responses into their underlying cell-cell and cell-protein interactions
SCIENTIFIC HYPOTHESIS
Systems-level analyses of immune cell composition and functional responses can reveal distinct cellular networks and pathways related to immune dysregulation in patients with systemic inflammation and immune dysregulation of unknown cause providing new targets for treatment and facilitating diagnosis
Inter-individual variation in systemic inflammatory diseases could be explained by differences in microbial colonization We hypothesize that microbiome compositional differences can explain differences among patients with defects in similar immune system pathways
By combining systems-level functional analyses with whole genome sequencing clinical analyses we can better understand redundant pathways in human immune systems which modulate phenotypes in patients with systemic inflammatory and immune dysregulation diseases
Immune dysregulation encompasses multiple different conditions in which the immune system does not function properly and displays inappropriate or inadequate responses overreactions or under-reactions directed towards external or internal targets It is a broad term and its manifestations include several different categories of disease
Immunodeficiencies These disorders impair the immune systems ability to defend the body against foreign or abnormal cells that invade or attack it such as bacteria viruses fungi and cancer cells As a result unusual bacterial viral or fungal infections or lymphomas or other cancers may develop Primary immunodeficiencies PIDs comprise a group of nearly 500 inherited disorders often due to single-gene mutations that result in the specific impairments in immune function Secondary immunodeficiencies SIDs involve a weakened immune system caused by external sources eg chemical chemotherapy infection HIV or cancer
Autoimmune Disorders In these conditions the production of autoantibodies against self-antigens causes the immune system to attack healthy cells and tissues Some of the most common examples include type 1 diabetes T1D rheumatoid arthritis RA multiple sclerosis MS systemic lupus erythematosus SLE
Autoinflammatory Disorders Here dysregulation of the innate immune system leads to spontaneous and recurrent inflammatory episodes In contrast to autoimmune diseases where antibodies against self-antigens play a central role the defect in autoinflammatory diseases often lies in the first responder innate arm of the immune system where the defect triggers inappropriate activation of the normal inflammatory response or disables resolution thereof Examples include familial Mediterranean fever FMF and cryopyrin-associated periodic syndromes
Severe allergies Allergic reactions are misdirected reactions of the immune system to substances commonly found in the environment Allergens elicit a T helper 2 immune response including the involvement of IgE mast cells innate lymphoid cells 2 ILC2 eosinophils and basophils Severe Allergy which does not respond to therapy can also indicate underlying immundysregulation
Lymphoproliferation Lymphoproliferation LP refers to persistent polyclonal oligoclonal or monoclonal proliferation of lymphoid cells in the clinical setting of immune dysregulation Symptoms are non-specific and mimic those of an infection inflammation or neoplasia and are characterized by chronic or recurrent lymphadenopathy hepatosplenomegaly extranodal infiltration andor peripheral blood lymphocytosis Immune disorders characterized by LP include autoimmune lymphoproliferative syndrome ALPS and X-linked lymphoproliferation XLP
Attempting to classify and group disorders of immune dysregulation in this way is of course an over-simplification as exemplified by conditions with both autoimmune and autoinflammatory components such as psoriasis or IBD For this reason it has been proposed that manifestations of immune dysregulation should be considered as a continuum with rare monogenic autoimmune disorders at one end rare monogenic autoinflammatory disorders at the other end followed by polygenic autoimmuneautoinflammatory conditions respectively with mixed pattern diseases in the center In real life patients with immune dysregulation also often present with more than one disease manifestation which further complicates diagnosis and treatment
Finally another factor that must be considered when trying to understand immune dysregulation is the influence of the microbiome Disruptions to the microbiota early in life are known to have lasting health effects including increased risks of immune- mediated diseases such as allergy However less is known about the possibility that inborn errors of immunity may also shape the developing microbiome with ensuing health-related consequences although the role of the microbiome in immune dysfunction is beginning to be appreciated For example impaired immunity may alter the intestinal microbiome causing subsequent increased intestinal permeability with increased exposure to bacterial DNA and an activation of innate and adaptive immune that ultimately perpetuate or exacerbate any defects in immunity
THE PROBLEM Certain types of immune dysregulation can be extremely rare and diagnosis and appropriate treatment are complicated issues Some are caused by specific genetic mutations with on average one new genetic mutation associated with immune dysregulation being discovered every month However in over half of patients with eg autoinflammatory disorders no genetic cause can be found Some disorders also affect multiple branches of the immune system due to a broader inappropriate immune response where signs and symptoms of autoimmunity allergy andor immunodeficiency can all be present in one condition at the same time A new approach is therefore essential to facilitate diagnosis and personalized treatment of patients with immune dysregulation which we believe will involve more holistic systems-level analyses of immune cell composition and functional responses Furthermore little is known about the interaction between the immune function and microbiome composition particularly in relation to immune dysregulation and understanding this interplay may reveal new therapeutic opportunities and enable prediction of adverse outcomes
SYSTEMS IMMUNOLOGY The human immune system consists of many specialized cell populations that stimulate each other to respond but also compete for growth factors and directly suppress each other to prevent immune pathology In this way the whole system functions as a highly integrated network Since this network is decentralized without any master regulator all actions in the system both productive immune responses to microbes and destructive autoimmune attacks on normal tissues emerge from the combined actions of the many immune cell populations that make up this network To understand higher order functions in a system this complex comprehensive analyses involving all cell populations simultaneously are required Only then can the consequence of activating one or a few specific cell populations in the system as a whole be understood This realization has led to the pursuit of Systems Immunology the application of technologies and theories from the field of Systems Biology to understand immune systems Technological advances primarily in mass cytometry for high- dimensional immune cell analysis and high-throughput serum protein analyses now allow for such detailed profiling of all components that make up human immune systems We therefore now have the ability to dissect immune responses into their underlying cell-cell and cell-protein interactions
SCIENTIFIC HYPOTHESIS
Systems-level analyses of immune cell composition and functional responses can reveal distinct cellular networks and pathways related to immune dysregulation in patients with systemic inflammation and immune dysregulation of unknown cause providing new targets for treatment and facilitating diagnosis
Inter-individual variation in systemic inflammatory diseases could be explained by differences in microbial colonization We hypothesize that microbiome compositional differences can explain differences among patients with defects in similar immune system pathways
By combining systems-level functional analyses with whole genome sequencing clinical analyses we can better understand redundant pathways in human immune systems which modulate phenotypes in patients with systemic inflammatory and immune dysregulation diseases
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None