J Chain Immune Molecule Traced to CXCL Chemokine Origins

Author: Pennsylvania State University
Published: 30 Jan 2024 - Updated: 4 Nov 2026
Publication Details: Peer-Reviewed | Experimental Study

Table of Contents:
Synopsis - Definition - Overview - FAQs - Insights, Updates - Related Content

Synopsis

This research, a peer-reviewed study published in Proceedings of the National Academy of Sciences by scientists at Penn State, the University of Maryland and the University of Chicago, identifies the evolutionary origin of the immunoglobulin joining chain, known as the J chain. Main findings show that the J chain, which assembles and stabilizes IgM and IgA antibodies and helps move them across mucosal tissues in the gut, nose and lungs, arose from the CXCL chemokine family that guides white blood cells around the body. Because the genes share no obvious sequence similarity, the link was found through matching gene structure, including the same number of exons, the same intron phases and a shared cysteine-X-cysteine motif. It matters because the J chain has puzzled immunologists since it was first described more than 50 years ago, and understanding how immune molecules are repurposed could inform future therapies, including personalized immune treatments relevant to people with immune disorders.*

At a Glance

• 1 - The J chain first appeared in jawed vertebrates.
• 2 - No other gene in the human secretome shares all three structural features.
• 3 - The team plans to test whether chemokines have taken on other immune roles.
• 4 - The link emerged after Flajnik emailed Kawasaki about a different gene family, which turned out to be unrelated.

Topic Definition

J Chain

The J chain, short for joining chain, is a small protein produced by antibody-secreting plasma cells that links individual antibody units together to form polymeric immunoglobulin M (IgM) and immunoglobulin A (IgA). By binding these units, the J chain controls the shape of the finished antibody and allows it to attach to the polymeric immunoglobulin receptor, which carries the antibodies across epithelial cells into mucus, tears, saliva and breast milk, where they help protect mucosal surfaces from infection.

Overview

Biological systems can behave as siblings in several ways, including by borrowing something and never giving it back. That appears to be what the human immune system did with a protein that now helps bind and regulate the subunits that make up antibodies, according to a multi-institute research collaboration. They found that, before the immune system evolutionarily co-opted it, the protein originally belonged to a gene family responsible for directing cells to move to the right location at the right time to address specific functional needs.

The researchers, including Kazuhiko Kawasaki, associate research professor of anthropology at Penn State, published their findings in the Proceedings of the National Academy of Sciences. According to the team, while this work primarily informs a fundamental understanding of one feature of the immune system and associated genes, it may also help open design pathways for future therapeutics, such as personalized immune responses.

"Everything comes from somewhere, and we believe we found the origin of immunoglobulin Joining chain (J chain), an important immune molecule," said corresponding author Martin F. Flajnik, department of microbiology and immunology, University of Maryland, who led the study. Flajnik also earned his undergraduate degree in biology from Penn State in 1978 before completing his graduate degrees at the University of Rochester.

The J chain assembles and stabilizes two types of antibodies, called immunoglobulin M (IgM) and immunoglobulin A (IgA). It specifically regulates the structures of the IgM and IgA molecules, which have several subunits, and is required for their movement across the mucus-producing tissue lining body structures with external exposure, like the intestine, nasal cavity and lungs. The researchers found that the J chain originated from the CXCL chemokines, a specific family of proteins that regulate the ability of white blood cells to move throughout the body.

"Like immunoglobulin itself and human-like adaptive immunity, the J chain emerged in jawed vertebrates, but its origin has remained mysterious since its discovery over 50 years ago," Flajnik said. "This finding was never anticipated. Chemokine-driven locomotion is a vital function of the immune system, but a totally different function as compared to the J chain!"

Evolutionarily, new genes are often generated from genes that reside physically close together on the chromosome, and those genes typically remain clustered together even as they evolve different yet similar functions, but Kawasaki said location isn't the only deciding factor to determine origin.

"The evolutionary relationship of genes can usually be detected when two genes retain similar nucleotide sequences or encoded amino acid sequences," Kawasaki said, referring to the materials comprising an organism's genetic code. "But previous studies could not detect any genes that show sequence similarities to the J chain gene, probably because the J chain gene sequence was quickly changed at its origin."

Flajnik said he had a hunch that the J chain was related to a group of secretory calcium-binding phosphoprotein (SCPP) genes due to their similar charges and levels of proline, an amino acid. He knew Kawasaki was an expert on SCPP genes, so he emailed him to assess the idea.

"He told me that, for various good reasons, the SCPPs and J chain were not related," Flajnik said. "That was sad, as it was my favorite hypothesis."

However, Kawasaki had noticed that genes on the opposite side of the J chain gene, away from the SCPP genes, did appear to be related to the J chain. Those were the CXCL chemokine genes.

"I immediately checked these CXCL chemokine genes and found that, though these genes do not show sequence similarities to the J chain genes, these genes and the J chain gene resemble each other with other various characteristics," Kawasaki said.

Those characteristics include the same number of exons, which encode the protein, and phases of introns, which act as interrupters to stop or start splicing of the RNA molecules transcribed from the gene. The second exon encodes the same sequence, which is known as the classical tripeptide Cysteine-X-Cysteine, for both genes. The lengths of three of the exons are also similar.

"No other gene encoding the human secretome, which encompasses all proteins that can be secreted by cells of an organism, shares all three characteristics," Kawasaki said.

The bonds between the Cysteine molecules encoded by the second exon in each gene are completely different from one another, though, the researchers said.

"This means that a chemokine can change its structure, to a large extent, and take on a new function," Flajnik said.

Next, the researchers said they plan to investigate if chemokines have taken on other functions, specifically in the immune system. They also want to study if chemokines are pliable in their structure, which could indicate the ability to take on an entirely new secondary structure, adapting in response to different biological needs as required.

"I've been around for a long time, for 44 years in science, but this experience was one of the most incredibly satisfying and lucky," Flajnik said. "I doubt that this similarity would have been uncovered for a long time without the serendipitous interaction between Kazuhiko and me."

The Research

Other co-authors include Yuko Ohta, assistant professor of microbiology and immunology at the University of Maryland, and Caitlin D. Castro, a research fellow in the Department of Biochemistry and Molecular Biology at the University of Chicago.

The National Institutes of Health supported this research.

Frequently Asked Questions

NOTE: Researched FAQs by Disabled World (DW)

What is the difference between IgM and IgA?

IgM is usually the first antibody made during a new infection and circulates mainly in the blood. IgA is the main antibody in mucous membranes and body secretions such as saliva, tears and breast milk.

What are chemokines?

Chemokines are small signaling proteins that attract and guide immune cells to sites of infection or injury. They also help organize the movement of cells during development and normal immune surveillance.

What does immunoglobulin mean?

Immunoglobulin is the scientific name for an antibody, a Y-shaped protein made by B cells that recognizes specific targets such as bacteria and viruses. Humans have five main classes, IgG, IgA, IgM, IgE and IgD.

What are exons and introns?

Exons are the parts of a gene that are kept and used to build a protein, while introns are stretches that are removed when the RNA copy is processed. Comparing their number and arrangement can reveal relationships between genes.

What is IgA deficiency?

Selective IgA deficiency is the most common primary immune deficiency, in which a person has very low or absent IgA. Many people have no symptoms, while others have more frequent respiratory or digestive infections.

Why do scientists study the evolution of immune genes?

Tracing how immune genes arose shows how different parts of the immune system fit together and why they work as they do. This knowledge can guide the design of vaccines and antibody-based treatments.

What are jawed vertebrates?

Jawed vertebrates, or gnathostomes, include sharks, bony fish, amphibians, reptiles, birds and mammals. They are the earliest group known to have an adaptive immune system based on antibodies and T cell receptors.

Is the J chain used in medicine?

The J chain is studied for engineering antibody drugs that can reach mucosal surfaces, such as IgA and IgM based therapies. Research in this area is still developing.

Insights, Analysis, and Developments

Editorial Note: Evolution often works by borrowing rather than inventing, and this study offers a clear example inside the human immune system. A protein family built to steer white blood cells became, over time, the clasp that holds antibodies together in the linings of the gut, airways and other mucosal surfaces where many infections begin. Mucosal antibodies such as IgA are a front line of defense, so knowing where their assembly machinery came from adds a missing piece to how vertebrate immunity was built. The finding is basic science, but basic science of this kind tends to underpin later work on vaccines, antibody drugs and treatments for people with immune deficiencies or chronic inflammatory conditions.*

Attribution/Source(s): This peer-reviewed publication was selected for publishing by the editors of Disabled World (DW) due to its relevance to the disability community. Originally issued as a press release by Pennsylvania State University and published on 30 Jan 2024. Last updated on 4 Nov 2026. This content may have been edited for style, clarity, or brevity.

* Editorial additions by Ian C. Langtree.