Proinflammatory and Immune

By

The latest study, "Long COVID Involves Activation of Proinflammatory and Immune Exhaustion Pathways," offers compelling evidence for a link between Long COVID and ME/CFS—a connection that has been hypothesized for years.

Summary:
Researchers studied gene activity in immune cells (PBMCs) from different groups of people, including those with long COVID (LC), those who had COVID but recovered fully (CC), and uninfected individuals. They found that:

People with long COVID showed higher levels of inflammation. Many inflammation-related genes, including those for cytokines and chemokines (like IL-6, IL-10, TNF, and others), were more active in the LC group.

Genes related to the NLRP3 inflammasome, complement system, and blood clotting were also more active in long COVID patients.

In contrast, genes that activate natural killer (NK) cells and T cells were less active in the LC group, suggesting reduced immune activation.

Between 3 to 6 months after infection, the LC group still had elevated inflammation-related gene activity and showed increased activity in pathways related to cytokine signaling (like IL-6 and interferons), JAK-STAT signaling, and immune cells like monocytes and neutrophils.

Meanwhile, genes involved in T cell activation and function were decreased, while markers of T cell exhaustion (like PD-1 signaling) were increased.

This suggests that in long COVID, chronic inflammation and dysfunctional T cells (especially exhausted CD8+ T cells) may play a key role.

The researchers also found that higher activity in IL-6 and JAK-STAT pathways was linked to less T cell activation and more T cell exhaustion, pointing to a possible mechanism behind long COVID symptoms.

The findings in the study of long COVID (LC) show patterns of chronic inflammation and immune system dysfunction. These immune features are not unique to long COVID and are also seen in several other related illnesses, especially those involving chronic immune activation, autoimmunity, or post-viral syndromes. Here are some key related illnesses:

Condition

What it is

Similarities with LC

Connection

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Complex chronic illness often triggered by infections

Persistent fatigue, cognitive impairment ("brain fog"), post-exertional malaise, immune abnormalities (T cell exhaustion, increased inflammation)

Some researchers believe long COVID may share mechanisms or overlap with ME/CFS

Autoimmune Diseases (e.g., Lupus, Rheumatoid Arthritis)

Conditions where immune system attacks body’s own tissues

Chronic inflammation, activation of cytokine pathways (IL-6, IFNs), T cell dysregulation

Some long COVID patients show signs of autoimmune activity, may trigger or unmask autoimmune disorders

Post-Viral Syndromes (e.g., after Epstein-Barr virus or SARS-CoV-1)

Chronic symptoms following viral infections

Fatigue, brain fog, joint pain, persistent immune activation long after virus clearance

Long COVID fits into broader category of post-viral illnesses

Persistent Viral Infections (e.g., HIV, EBV)

Infections that remain in body long time, often latent

Chronic immune system activation, T cell exhaustion (especially CD8+ T cells), upregulation of PD-1 and other exhaustion markers

Immune signature of long COVID (exhausted T cells) similar to chronic infections

Cytokine Release Syndrome (CRS) / Hyperinflammatory States

Condition where body releases too many cytokines quickly

High levels of IL-6, TNF, other cytokines, involvement of JAK-STAT signaling

CRS is usually acute, prolonged elevation of cytokines in long COVID suggests milder, chronic dysregulation

Fibromyalgia

Chronic condition with widespread pain, fatigue, cognitive issues

Brain fog, fatigue, sleep disturbances

 

Connection: Some long COVID patients meet criteria for fibromyalgia, and overlapping mechanisms such as nervous system sensitization may be involved.

Condition

Key Overlap with Long COVID

ME/CFS

Fatigue, brain fog, immune dysfunction

Autoimmune diseases

Chronic inflammation, T cell issues

Post-viral syndromes

Long-term symptoms after infection

Persistent viral infections

T cell exhaustion, PD-1 signaling

Cytokine release/hyperinflammation

High cytokines, JAK-STAT signaling

Fibromyalgia

Pain, fatigue, cognitive symptoms

Test Category

Test Name

Purpose/What it Assesses

Basic Blood Work

Complete Blood Count (CBC)

Checks for anemia, infection, and immune cell levels

Basic Blood Work

Comprehensive Metabolic Panel (CMP)

Assesses kidney and liver function, blood sugar, and electrolytes

Basic Blood Work

C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR)

General markers of inflammation

Basic Blood Work

Ferritin

Can be elevated in chronic inflammation

Basic Blood Work

Lactate Dehydrogenase (LDH)

May reflect tissue stress or inflammation

Immune and Inflammatory Markers

Cytokine Panel (including IL-6, IL-10, TNF-alpha, IFN-gamma)

Detects immune system overactivation

Immune and Inflammatory Markers

Immunoglobulin levels (IgG, IgA, IgM)

Evaluates immune function or chronic immune response

Immune and Inflammatory Markers

Antinuclear Antibody (ANA) and Autoantibody Panels

Screens for autoimmune diseases

Immune and Inflammatory Markers

Complement proteins (C3, C4)

Assesses immune activation and potential autoimmune activity

Immune and Inflammatory Markers

Flow Cytometry (if available)

Measures immune cell populations and can identify T cell exhaustion or NK cell abnormalities

Cardiopulmonary Testing

Electrocardiogram (ECG)

Checks for heart rhythm abnormalities

Cardiopulmonary Testing

Echocardiogram

Evaluates heart structure and function

Cardiopulmonary Testing

Cardiac Biomarkers (e.g., troponin, BNP)

Detects heart muscle stress or damage

Cardiopulmonary Testing

Pulmonary Function Tests (PFTs)

Assesses lung function

Cardiopulmonary Testing

Chest X-ray or CT scan

Rules out lung damage or lingering inflammation

Cardiopulmonary Testing

Exercise Tolerance Testing or 6-Minute Walk Test

Measures stamina and oxygen levels during exertion

Neurological and Cognitive Testing

Cognitive screening tests (e.g., MoCA)

Evaluate attention, memory, and executive function

Neurological and Cognitive Testing

Brain MRI

Used when neurological symptoms are severe or worsening

Neurological and Cognitive Testing

Electroencephalogram (EEG)

May be used if seizures or abnormal brain activity are suspected

Endocrine and Metabolic Testing

Thyroid Function Tests (TSH, Free T4, Free T3)

Identifies thyroid imbalances

Endocrine and Metabolic Testing

Cortisol and ACTH

Assesses adrenal gland function

Endocrine and Metabolic Testing

Hemoglobin A1c and Fasting Glucose

Screens for prediabetes or insulin resistance

Endocrine and Metabolic Testing

Vitamin D, Vitamin B12, Folate

Identifies nutrient deficiencies that may contribute to fatigue or neurological symptoms

Optional or Specialist-Ordered Tests

Testing for viral persistence (e.g., residual SARS-CoV-2 RNA)

Still investigational

Optional or Specialist-Ordered Tests

Microclot detection (e.g., fibrin amyloid microclots)

Currently in research settings

Optional or Specialist-Ordered Tests

Tilt Table Test

Evaluates autonomic dysfunction, often used for patients with dizziness or POTS-like symptoms

Optional or Specialist-Ordered Tests

Stool analysis or microbiome profiling

Investigational, explores gut-immune connections

Summary

There is no single test to diagnose long COVID. Testing should be guided by the patient's symptoms and used to rule out other conditions, assess inflammation and immune dysregulation, and guide treatment. A stepwise approach beginning with basic labs and expanding to specialized testing as needed is recommended. Specialist referrals may be appropriate in complex cases.

Reference:
Long COVID involves activation of proinflammatory and immune exhaustion pathways
https://www.nature.com/articles/s41590-025-02353-x


© 2025-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

Comments

Post a Comment

Popular posts from this blog

Schnitzler Syndrome: A Rare Autoinflammatory Disorder

By
Schnitzler syndrome is a rare, chronic autoinflammatory disease characterized by chronic urticaria (hives), recurrent fever, joint pain, and monoclonal gammopathy (abnormal proteins in the blood). First described by Dr. Liliane Schnitzler in 1972 , this condition is often misdiagnosed, leading to years of untreated symptoms before a correct diagnosis is made. The case report, " A 58-Year-Old Woman With Urticaria, Fever, and Joint Pain " , describes a case that closely aligns with my own experience with this challenging disorder. Key Features of Schnitzler Syndrome Schnitzler syndrome presents with a characteristic set of symptoms, though not all patients experience them in the same way: Chronic Urticaria (Hives) – Persistent, non-itchy or mildly itchy red patches that do not respond to antihistamines. Monoclonal Gammopathy (IgM or IgG type) – Abnormal monoclonal immunoglobulin detected in the blood (most commonly IgM ). Recurrent Fever – Unexplained fever episodes, often...
Read more

Acute Flaccid Myelitis (AFM): Understanding the “Polio-like” Illness Affecting the Spinal Cord

By
Acute flaccid myelitis (AFM) is a rare but serious neurological disorder that primarily affects children and results in sudden weakness or paralysis in the limbs. Often referred to as a “polio-like” illness, AFM has drawn growing attention over the past decade due to its similarities with poliomyelitis and its seasonal spikes in reported cases. While AFM remains uncommon, its potential severity—and the uncertainty surrounding its causes—make it an important condition for clinicians, parents, and public health officials to understand. What Is Acute Flaccid Myelitis? AFM is a condition that affects the gray matter of the spinal cord , where it damages motor neurons responsible for muscle movement. This leads to acute, flaccid paralysis , meaning muscles become limp and weak, often without warning. The condition can progress rapidly, and in some cases, the weakness can become long-lasting or even permanent. Although its symptoms resemble those of poliovirus infection, AFM is not cau...
Read more

Dysferlin Protein: Key Roles, Genetic Locations

By
Image
The purpose of this article is to share and discuss the details of a new discovery, which is highlighted within: CRISPR-Cas9: A Breakthrough Tool to Repair the DYSF Gene The dysferlin protein plays an essential role in maintaining the integrity of muscle cell membranes, particularly in tissues that endure significant mechanical stress, such as skeletal and cardiac muscles . Encoded by the DYSF gene , dysferlin is indispensable for repairing damaged cell membranes after injury caused by muscle contraction or external forces. This article explores the main locations where dysferlin is produced, its role in muscle repair, and supportive nutritional and therapeutic strategies for individuals with dysferlin deficiency, such as those affected by dysferlinopathies (e.g., Limb-Girdle Muscular Dystrophy Type 2B or Miyoshi Myopathy). Currently, there is no definitive answer as to why the severity of dysferlin protein expression or depletion varies. Do pathogens play a role in the methylation o...
Read more