Reproductive Immunology: A Foundational Insight into Reproductive Failure

Why Surgical Evaluation May Be the Most Effective Next Step

At BRI/ESSI, our team has spent years deeply engaged in the science of reproductive immunology, investigating how inflammation, immune dysfunction, and autoimmune disease can contribute to miscarriage, implantation failure, and infertility. Our previous immunological program was among the most advanced in the world, offering a wide-ranging set of diagnostic tools to evaluate underlying immune conditions—often in cases labeled “unexplained” by other centers.

After 30 years as a Reproductive Endocrinologist, our Medical Director Dr. Andrea Vidali understands the crucial role Endometriosis can play as an underlying condition causing multiple failures and pregnancy losses. Dr. Vidali has learned that for many patients, the missing link is not more testing—it’s a thorough surgical evaluation. Through expert excision of Endometriosis or correction of structural abnormalities, we’ve helped women who previously suffered repeated pregnancy losses have had great success, carrying healthy pregnancies to term.

As such, BRI/ESSI has evolved to become an Exclusive Endometriosis Treatment Center addressing the need for a hands-on and personal approach for the Diagnosis and Treatment of Endometriosis and the role it plays in Infertility.

While we no longer offer immunological testing or treatment services, our experience in this field continues to guide our understanding of the hidden drivers behind reproductive challenges. In particular, we have seen time and again how underlying conditions such as Endometriosis and Adenomyosis—often inflammatory in nature—play a critical role in reproductive failure and frequently go undiagnosed without surgery.

Understanding the Immune System’s Role in Reproductive Health

Many patients with autoimmune or inflammatory conditions (including PCOS and Endometriosis) may not exhibit typical symptoms. Instead, the inability to conceive or sustain a pregnancy may be the only visible sign of immune dysfunction. Scientific literature shows that immune dysregulation often begins long before overt symptoms appear, which is why a diagnosis may be missed in standard fertility workups.

In previous years, our reproductive immunology program performed a comprehensive range of tests to uncover these subtle immune issues. While we no longer perform these tests, we believe it's important to share what a truly in-depth immune investigation looks like—especially in contrast to the limited panels offered by many centers.

Legacy of Testing at ESSI/BRI: What True Immune Evaluation Entailed

Killer Immunoglobulin Receptor (KIR) Genes

  • KIR2DL1
  • KIR2DL2
  • KIR2DL3
  • KIR2DL4
  • KIR2DL5
  • KIR3DL1
  • KIR3DL2
  • KIR3DL3
  • KIR2DS1
  • KIR2DS2
  • KIR2DS3
  • KIR2DS4
  • KIR2DS5
  • KIR3DS1

Certain maternal KIR haplotypes in combination with maternal and paternal HLA-C genotypes can result in a failure in embryo implantation or defective placentation leading to miscarriage or later pregnancy complications including preeclampsia, intrauterine growth restriction (IUGR), or stillbirth.

Human Leukocyte Antigen (HLA) Haplotyping (Patient and Partner/Sperm Donor)

  • Class I: HLA-A, HLA-B, HLA-C
  • Class II (includes whether class II HY-restricting HLA (HYrHLA) alleles are present): HLA-DQa1, HLA-DQb1, HLA-DRB1, HLA-DRB3/4/5
  • HLA-G 14 bp ins/del

Many HLA alleles and haplotypes predispose to autoimmune conditions, Endometriosis, and PCOS that can affect the ability to become or stay pregnant. Proper analysis of HLA allele mismatching is far more involved than simply looking at the DQA1 locus.

Intracellular Cytokine Testing

CD4+ T cells: TNFα (CD3+/4+/TNFα+), IFNγ (CD3+/4+/IFNγ+), IL-17, IL-4, IL-10

CD8+ T cells: TNFα (CD3+/8+/TNFα+), IFNγ (CD3+/8+/IFNγ+), IL-17, IL-4, IL-10

NKT cells: TNFα (CD3+/56+/TNFα+), IFNγ (CD3+/56+/IFNγ+), IL-17, IL-4, IL-10

NK cells: TNFα (CD3+/56-/TNFα+), IFNγ (CD3+/56-/IFNγ+), IL-17, IL-4, IL-10

We determine percentages and ratios across cell types and cytokines. Patterns help distinguish types of immune abnormalities (e.g., Th1/Th2 bias) that guide appropriate treatments.

Complete Blood Count (CBC) With Differential

  • WBC, RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, Platelet Count
  • Absolute Neutrophils, Monocytes, Eosinophils, Basophils
  • Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils

Abnormalities can indicate underlying immune conditions (e.g., low neutrophils suggesting autoimmune neutropenia).

NK Cell Cytotoxic Activity

  • E:T 50:1 Native State
  • E:T 25:1 Native State
  • E:T 12.5:1 Native State
  • E:T 25:1 + IL-2 Stimulation
  • E:T 25:1 + Intralipid
  • E:T 25:1 + 12.5 mg/dl IgG
  • E:T 25:1 + 6.25 mg/dl IgG

NKa can be useful as part of a broader workup but is inadequate by itself and frequently misinterpreted.

Reproductive Immunophenotype

  • Total T cells (CD3+), Total NKT (CD3+/56+), Total NK (CD3-/56+)
  • CD16+ and CD16- NK subsets
  • CD4+ and CD8+ T cells; Activated subsets (CD3+/4+/25+, CD3+/25+), CD28+ T cells
  • Total B cells (CD19+), B1a B cells (CD19+/5+)
  • Activated T cells (CD3+/HLA-DR+)
  • Regulatory T cells (CD3+/4+/25hi/127lo/FoxP3+)

Anti-HLA Antibodies

  • HLA Class I (HLA-A, -B, -C)
  • HLA Class II (HLA-DQA1, -DQB1, -DRB1, -DRB3/4/5)
  • Complement (C1q) fixation

Single antigen bead assays define antibody profiles and significance, including partner-specific reactivity and C1q fixation.

Serum Cytokines

  • TNFα, IL-6, IL-8, IL-17, TGFβ-1/2/3

Autoantibody Testing

  • Antinuclear and antiphospholipid antibodies
  • Thyroid autoantibodies: Anti-TPO, Anti-thyroglobulin, Anti-TSH receptor
  • Rheumatoid factor, Anti-CCP

Other

  • C3 and C4 complement activity
  • Total IgM, IgA, IgG, IgE
  • Vitamin D, Homocysteine
  • MTHFR polymorphisms (C677T, A1298C)
  • TSH

These analytes reveal immune/inflammatory disorders and important deficiencies (e.g., vitamin D), and assess folate metabolism.

Why ESSI Now Focuses on Surgical Intervention

After years of analyzing immune data and treating thousands of patients, our conclusion is clear: while immune dysfunction is real and impactful, for many patients—especially those with recurrent miscarriage, IVF failure, or unexplained infertility—the root cause is anatomical and inflammatory, and best addressed through expert surgical intervention, not just more testing.

Conditions like Endometriosis and Adenomyosis are not always visible on ultrasound or MRI, nor can they be confirmed through blood tests. These conditions often trigger chronic inflammation and immune dysfunction, but the only definitive way to diagnose and treat them is through minimally invasive excision surgery—our center’s primary focus.

The ESSI Difference: A Path Forward

If you have experienced:

  • Recurrent miscarriage
  • Multiple failed IVF cycles
  • “Unexplained” infertility
  • Or a family history of autoimmune/inflammatory disease

…then the next step may not be another lab test, but rather a thorough surgical evaluation with our team at ESSI.

We believe patients deserve more than vague answers like “bad luck.” Our center provides a clear, strategic path built on science, precision surgery, and compassionate care.

Request a Consultation to learn whether surgical intervention could provide the answers and outcomes you’ve been seeking.